Cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes

ABSTRACT

The present invention provides novel pyrazoles that are useful as cannabinoid receptor antagonists and pharmaceutical compositions thereof and methods of using the same for treating obesity, diabetes, and/or cardiometabolic disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority benefit under 35 U.S.C. §119(e)of U.S. Provisional Patent Application Ser. No. 60/798,001 filed May 5,2006. The disclosure this application is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention provides cannabinoid receptor antagonists/inverseagonists and pharmaceutical compositions thereof and methods of usingthe same for treating obesity, diabetes, and/or cardiometabolicdisorders. The present invention also relates to a novel method fortreating obesity, diabetes, and/or cardiometabolic disorders using apyrazoline.

BACKGROUND OF THE INVENTION

Obesity is associated with an increase in the overall amount of adiposetissue (i.e., body fat), especially adipose tissue localized in theabdominal area. Obesity has reached epidemic proportions in the UnitedStates. The prevalence of obesity has steadily increased over the yearsamong all racial and ethnic groups. The most recent data from theCenters for Disease Control and Prevention, and the National Center forHealth Statistics report 66% of the adult population overweight (BMI,25.0-29.9), 31% obese (BMI, 30-39.9), and 5% extremely obese(BMI, >40.0). Among children aged 6 through 19 years, 32% are reportedas overweight and 17% as obese. This translates to 124 million Americansmedically overweight, and 44 million of these deemed obese. Obesity isresponsible for more than 300,000 deaths annually, and is one of theleading causes of preventable death in the United States. Obesity is achronic disease that contributes directly to numerous dangerousco-morbidities, including type 2 diabetes, cardiovascular disease,inflammatory diseases, premature aging, and some forms of cancer. Type 2diabetes, a serious and life-threatening disorder with growingprevalence in both adult and childhood populations, is currently the7^(th) leading cause of death in the United States. Since more than 80%of patients with type 2 diabetes are overweight, obesity is the greatestrisk factor for developing type 2 diabetes. Increasing clinical evidenceindicates that the best way to control type 2 diabetes is to reduceweight.

The most popular over-the counter drugs for the treatment of obesity,phenylpropanolamine and ephedrine, and the most popular prescriptiondrug, fenfluramine, were removed from the marketplace as a result ofsafety concerns. Drugs currently approved for the long-term treatment ofobesity fall into two categories: (a) CNS appetite suppressants such assibutramine and (b) gut lipase inhibitors such as orlistat. CNS appetitesuppressants reduce eating behavior through activation of the ‘satietycenter’ in the brain and/or by inhibition of the ‘hunger center’ in thebrain. Gut lipase inhibitors reduce the absorption of dietary fat fromthe gastrointestinal (GI) tract. Although sibutramine and orlistat workthrough very different mechanisms, they share in common the same overallgoal of reducing body weight secondary to reducing the amount ofcalories that reach the systemic circulation. Unfortunately, theseindirect therapies produce only a modest initial weight loss(approximately 5% compared to placebo) that is usually not maintained.After one or two years of treatment, most patients return to or exceedtheir starting weight. In addition, most approved anti-obesitytherapeutics produce undesirable and often dangerous side effects thatcan complicate treatment and interfere with a patient's quality of life.

The lack of therapeutic effectiveness, coupled with the spiralingobesity epidemic, positions the ‘treatment of obesity’ as one of thelargest and most urgent unmet medical needs. There is, therefore, a realand continuing need for the development of improved medications thattreat or prevent obesity.

The endocanabinoid system, comprised of the canabinoid receptors (CB1and CB2) and their endogenous ligands (e.g., anandamide, 2-AG), plays aprominent role in the control of food intake and energy metabolism. CB1receptors are widely expressed in the brain, including cortex,hippocampus, amygdala, pituitary and hypothalamus. CB1 receptors havealso been identified in numerous peripheral organs and tissues,including thyroid gland, adrenal gland, reproductive organs, adiposetissue, liver, muscle, and gastrointestinal tract. CB2 receptors arelocalized almost exclusively in immune and blood cells, see EndocrineReviews 2006, 27, 73.

The plant-derived cannabinoid agonist Δ⁹-tetrahydrocannabinol (Δ⁹-THC),the main psychoactive component of marijuana, binds to both CB1 and CB2receptors. Δ⁹-THC is widely reported to increase appetite and foodintake (hyperphagia) in humans and in animals. This hyperphagic effectis largely blocked by pretreatment with selective CB1 receptorantagonists/inverse agonists [e.g., rimonabant (SR141716A, Acomplia®)],strongly supporting the belief that CB1 receptor activation mediates thehyperphagic effect of Δ⁹-THC, see Endocrine Reviews 2006, 27, 73.

In humans, rimonabant produces a clinically meaningful weight loss inobese patients. Patients also experience improvements in diabetes and inassociated cardiometabolic risk factors, including a decrease intriglyceride levels. Rimonabant also produces greater reductions inabdominal fat deposits, which are a known risk factor for diabetes andheart disease. Taken together, these improvements in adiposity,diabetes, and cardiometabolic risk factors produce an overall decreasein the prevalence of the metabolic syndrome, see Lancet 2005, 365,1389-97 and NEJM 2005, 353, 2121.

The beneficial effects of rimonabant on diabetes and cardiometabolicrisk factors such as high blood pressure and elevated levels oftriglycerides cannot be explained by diet and weight loss alone. Forexample, in patients receiving 20 mg of rimonabant, only approximately50% of the beneficial effects on triglycerides, fasting insulin, andinsulin resistance can be accounted for by weight loss. These resultssuggest a direct pharmacological effect of CB1 antagonists/inverseagonists on glucose and lipid metabolism, in addition to indirecteffects on metabolism secondary to hypophagia-mediated weight loss, seeScience 2006, 311, 323 and JAMA 2006, 311, 323.

The CB1 receptor is one of the most abundant and widely distributed Gprotein-coupled receptors in the mammalian brain. It is believed thatthe appetite-suppressant properties of CB1 antagonists/inverse agonistsare mediated through an interaction with CB1 receptors in thehypothalamus (regulation of food intake), and in the mesolimbic region(rewarding properties of food). However, CB1 receptors are far morebroadly distributed in brain (e.g., neocortex, hippocampus, thalamus,cerebellum, and pituitary), and while interacting with targeted CB1receptors in hypothalamus and mesolimbic regions, CB1 antagonists haveready access to non-targeted CB1 receptors that have little if any rolein appetite control. Binding to non-targeted receptors can often lead tounwanted side effects of CNS drugs [Endocrine Reviews 2006, 27: 73]. TheCB1 antagonist/inverse agonist rimonabant produces psychiatric andnervous system side effects. These include depressed mood, anxiety,irritability, insomnia, dizziness, and headache. These side effects aredose-related and are most pronounced at the most efficaciousweight-reducing dose of rimonabant (JAMA 2006, 311, 323). The occurrenceof therapeutic efficacy (appetite suppression) and side effects over thesame dose range strongly suggest that both effects are mediated throughconcurrent antagonism of CB1 receptors in both ‘targeted’ and‘non-targeted’ brain regions. Brain-penetrant CB1 antagonists do notselectively target CB1 receptors in efficacy brain regions, whileignoring CB1 receptors in side effect brain regions.

The beneficial effects of the CB1 antagonist/inverse agonist rimonabanton body weight, adiposity, diabetes, and cardiometabolic risk factorssuch as high blood pressure and elevated levels of triglycerides cannotbe explained by weight loss derived from CNS-mediated appetitesuppression alone, see JAMA 2006, 311, 323. Approximately 50% of thenon-CNS benefit is likely derived from an interaction with CB1 receptorsin peripheral tissues known to play an active role in metabolism. Theseinclude adipose tissue, liver, muscle, and gastrointestinal tract.

In view of the above, it is highly desirable to find effective andhighly selective CB1 receptor antagonists/inverse agonists with limitedor no CNS adverse side effects, including mood disorders. Particularly,it is desirable to find compounds that preferentially target CB1receptors in peripheral tissues (e.g., adipose tissue, liver, muscle,and gastrointestinal tract), while sparing CB1 receptors in brain. Inthis way, peripherally-mediated beneficial effects of CB1antagonists/invers agonists should be maintained, whereas CNS sideeffects should be reduced or eliminated. This should provide a novelopportunity to develop safer agents for the prevention or treatment ofobesity, diabetes, and cardiometabolic diseases (e.g., hypertension anddyslipidemias).

SUMMARY OF THE INVENTION

Accordingly, in an aspect, the present invention provides novelpyrazolines or pharmaceutically acceptable salts thereof that are CB1receptor antagonists.

In another aspect, the present invention provides novel pharmaceuticalcompositions, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt form thereof.

In another aspect, the present invention provides novel methods fortreating obesity, diabetes, and/or cardiometabolic disorders (e.g.,hypertension and dyslipidemias), comprising: administering to a patientin need thereof a therapeutically effective amount of at least one ofthe compounds of the present invention or a pharmaceutically acceptablesalt form thereof.

In another aspect, the present invention provides processes forpreparing novel compounds.

In another aspect, the present invention provides novel compounds orpharmaceutically acceptable salts for use in therapy.

In another aspect, the present invention provides the use of novelcompounds for the manufacture of a medicament for the treatment ofobesity, diabetes, and/or cardiometabolic disorders.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat the presently claimed compounds or pharmaceutically acceptable saltforms thereof are expected to be effective CB1 receptor antagonists.

DETAILED DESCRIPTION OF THE INVENTION

All references cited herein are hereby incorporated in their entiretyherein by reference.

The present invention is based on the finding that a CB1 receptorantagonist has beneficial effects on body weight, adiposity, diabetes,and cardiometabolic risk factors such as hypertension and dyslipidemiasthat cannot be explained by weight loss derived from CNS-mediatedappetite suppression alone and that this effect is mediated, at least inpart, through interaction at peripheral receptors. To this end, thepresent invention provides compounds that are designed to preferentiallytarget CB1 receptors in peripheral tissues (e.g., adipose tissue, liver,muscle, and gastrointestinal tract), while sparing CB1 receptors inbrain. Peripherally-mediated beneficial effects of CB1 antagonistsshould be maintained, whereas CNS side effects should be reduced oreliminated.

The compounds of the present invention have been designed to havereduced CNS exposure by virtue of their inability or limited ability topenetrate the blood-brain barrier (BBB) or by their participation inactive transport systems, thus reducing centrally mediated side-effects,a potential problem with many anti-obesity and anti-diabetic agents. Itis expected that the peripherally restricted compounds of the presentinvention will have no or very limited CNS effects. Thus, theirperipherally mediated CB1 antagonistic properties should providetherapeutic agents with greater safety, as previously demonstrated inearlier classes of peripherally restricted agents.

Moreover, if the maximum dosage of a drug used in the treatment ofobesity, diabetes, and/or cardiometabolic disorders (e.g., hypertensionand dyslipidemias) is limited as a result of CNS side effects (e.g.,seizures, depression, anxiety, movement disorders, and hyperactivity),incorporation of a peripherally restricting group in such a drug wouldlower the brain concentration of the drug relative to the concentrationin the systemic circulation, thereby affording the opportunity toincrease the dosage employed to treat the peripheral disorder. Theincreased dosage may provide greater therapeutic efficacy, as well as amore rapid onset of therapeutic action.

In an embodiment, the present invention provides novel compound AA or astereoisomer or pharmaceutically acceptable salt thereof:

wherein:

X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C₁₋₆ alkyl,halogen, CF₃, O—C₁₋₆ alkyl, NO₂, NR₂, O(CH₂)CO₂R, OCH₂CH═CHCO₂R,CH₂O(CH₂)_(n)CO₂R, CH₂OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂,CH₂O(CH₂)PO(OR)₂, NR^(a)(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)PO(OR)₂,NR^(a)CH₂CH═CHCO₂R, NR^(a)SO₂CH₃, NR^(a)CO(CH₂)_(n)CO₂R,NR^(a)CO(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C₆H₄CO₂R,O(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, CH₂O(CH₂)_(n)C₆H₄CO₂R,O(CH₂)_(n)C₆H₄CONR^(a) ₂, O(CH₂)_(n)C₆H₄(CH₂)_(n)CONH₂,O(CH₂)_(n)C₆H₄-tetrazole, CH₂O(CH₂)_(n)C₆H₄CONH₂,CH₂O(CH₂)_(n)C₆H₄-tetrazole, O(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole,NR^(a)(CH₂)_(n)C₆H₄CO₂R, CH₂NR^(a)(CH₂)_(n)C₆H₄CO₂R,NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂, CH₂NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂,NR^(a)(CH₂)_(n)C₆H₄-tetrazole, CH₂NR^(a)(CH₂)_(n)C₆H₄-tetrazole,C(NH)NH₂, (CH₂)_(n)C(NH)NH₂, O(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C(NH)NH₂,CH₂O(CH₂)_(n)CONR^(a) ₂, NR^(a)(CH₂)_(n)CONR^(a) ₂, OCH₂CH═CHCONH₂,CH₂OCH₂CH═CHCONR^(a) ₂, NR^(a)CH₂CH═CHCONR^(a) ₂, (CH₂)_(m)-tetrazole,O(CH₂)_(n)-tetrazole, O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, andSO₂NR^(a)CH₃;

Z is selected from: H, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, O(CH₂CH₂O)_(p)R,acetyloxy, propionyloxy, O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R,O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)CONH₂, O(CH₂)_(n)C(NH)NH₂, OCH₂CH═CHCONH₂,O(CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, andO(CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole;

Q is selected from: H, C₁₋₆ alkyl, (CH₂)_(n)-aryl, (CH₂)_(n)-heteroaryl,(CH₂)_(n)-tetrazole, CHA(CH₂)_(n)CO₂R, CHA(CH₂)_(m)CONR₂,(CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, (CH₂)_(n)-phenyl-(CH₂)_(m)CONH₂, and(CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole;

M is C═O or SO₂;

R is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl;

R^(a) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

A is selected from H, C₁₋₆ alkyl, (CH₂)_(m)-C₃₋₆-cycloalkyl, CH₂OH,CH(CH₃)OH, and (CH₂)_(m)-phenyl, wherein phenyl is substituted with 0-3groups selected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, and NO₂;

p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

m is selected from 0, 1, 2, and 3;

n is selected from 1, 2, and 3; and,

at least one of X, Y, X′, Y′, X″, Y″, Z, or Q is a group, is suitablymodified to be a group, or is replaced by a group capable of reducing orlimiting the CNS (brain) levels of compound AA.

[1] In an embodiment, the present invention provides novel compound ofFormula I or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C₁₋₆ alkyl,halogen, CF₃, O—C₁₋₆ alkyl, NO₂, NR₂, O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R,CH₂O(CH₂)_(n)CO₂R, CH₂OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂,CH₂O(CH₂)_(n)PO(OR)₂, NR^(a)(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)PO(OR)₂,NR^(a)CH₂CH═CHCO₂R, NR^(a)SO₂R, NR^(a)CO(CH₂)_(n)CO₂R,NR^(a)CO(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C₆H₄CO₂R,O(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, CH₂O(CH₂)_(n)C₆H₄CO₂R,O(CH₂)_(n)C₆H₄CONR^(a) ₂, O(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a) ₂,O(CH₂)_(n)C₆H₄-tetrazole, CH₂O(CH₂)_(n)C₆H₄CONR^(a) ₂,CH₂O(CH₂)_(n)C₆H₄-tetrazole, O(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole,NR^(a)(CH₂)_(n)C₆H₄CO₂R, CH₂NR^(a)(CH₂)_(n)C₆H₄CO₂R,NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂,CH₂NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂, NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a)₂, NR^(a)(CH₂)_(n)C₆H₄-tetrazole, CH₂NR^(a)(CH₂)_(n)C₆H₄-tetrazole,NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole, C(NH)NR₂, (CH₂)_(n)C(NH)NR₂,O(CH₂)_(n)CONR₂, O(CH₂)_(n)C(NH)NR₂, CH₂O(CH₂)_(n)CONR^(a) ₂,NR^(a)(CH₂)_(n)CONR^(a) ₂, OCH₂CH═CHCONR^(a) ₂, CH₂OCH₂CH═CHCONR^(a) ₂,NR^(a)CH₂CH═CHCONR₂, (CH₂)_(m)-tetrazole, O(CH₂)_(n)-tetrazole,O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, and SO₂NHCH₃;

Z is selected from: H, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, O(CH₂CH₂O)_(p)R,OC(O)—C₁₋₆ alkyl, O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂,O(CH₂)_(n)CONH₂, O(CH₂)_(n)C(NH)NH₂, OCH₂CH═CHCONH₂,O(CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, andO(CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole;

Q is selected from: H, C₁₋₆ alkyl, (CH₂)_(n)-aryl, (CH₂CH₂O)_(p)R,(CH₂)_(n)-heteroaryl, (CH₂)_(n)-tetrazole, —CHA(CH₂)_(m)C(O)NR₂,CHA(CH₂)_(m)CO₂R, (CH₂)_(n)-phenyl-(CH₂)_(n)CO₂R,(CH₂)_(n)-phenyl-(CH₂)_(m)CONH₂, and(CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole, wherein the heteroaryl, phenyl,and aryl are substituted with 0-3 groups selected from H, C₁₋₄ alkyl,halogen, CF₃, O—C₁₋₄ alkyl, and NO₂;

M is C═O or SO₂;

R is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl;

R^(a) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

A is selected from H, C₁₋₆ alkyl, (CH₂)_(m)C₃₋₆-cycloalkyl, CH₂OH,CH(CH₃)OH, and (CH₂)_(m)-phenyl, wherein the phenyl is substituted with0-3 groups selected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, andNO₂;

p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

m is selected from 0, 1, 2, and 3; and,

n is selected from 1, 2, and 3;

provided that at least one of the following is satisfied:

(a) at least one of X, Y, X′, Y′, X″, and Y″ is other than H, C₁₋₆alkyl, halogen, CF₃, O—C₁₋₆ alkyl, NO₂, and NR₂;

(b) Z is other than H, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, acetyloxy, andpropionyloxy; or,

(c) Q is other than H, C₁₋₆ alkyl, (CH₂)_(n)-heteroaryl, and(CH₂)_(n)-aryl.

It can be desirable for at least one of X, Y, X′, Y′, X″, and Y″ to beother than H, C₁₋₆ alkyl, halogen, CF₃, O—C₁₋₆ alkyl, NO₂, and NR₂.

[2] In another embodiment, the present invention provides novelcompounds of formula I or a stereoisomer or pharmaceutically acceptablesalt thereof, wherein:

at least one of X, Y, X′, Y′, X″, and Y″ is independently selected from:O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, CH₂O(CH₂)_(n)CO₂R, CH₂OCH₂CH═CHCO₂R,O(CH₂)_(n)PO(OR)₂, CH₂O(CH₂)_(n)PO(OR)₂, NR^(a)(CH₂)_(n)CO₂R,NR^(a)(CH₂)_(n)PO(OR)₂, NR^(a)CH₂CH═CHCO₂R, NR^(a)CO(CH₂)_(n)CONR^(a) ₂,NR^(a)SO₂CH₃, NR^(a)CO(CH₂)_(n)CO₂R, O(CH₂)_(n)C₆H₄CO₂R,O(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, CH₂O(CH₂)_(n)C₆H₄CO₂R, O(CH₂)_(n)C₆H₄CONH₂,O(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C₆H₄-tetrazole,CH₂O(CH₂)_(n)C₆H₄CONH₂, CH₂O(CH₂)_(n)C₆H₄-tetrazole,O(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole, NR^(a)(CH₂)_(n)C₆H₄CO₂R,CH₂NR^(a)(CH₂)_(n)C₆H₄CO₂R, NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R,NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂, CH₂NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂,NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a) ₂, NR^(a)(CH₂)_(n)C₆H₄-tetrazole,CH₂NR^(a)(CH₂)_(n)C₆H₄-tetrazole,NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole, C(NH)NR₂, (CH₂)_(n)C(NH)NR₂,O(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C(NH)NH₂, CH₂O(CH₂)_(n)CONR^(a) ₂,NR^(a)(CH₂)_(n)CONH₂, OCH₂CH═CHCONR^(a) ₂, CH₂OCH₂CH═CHCONR^(a) ₂,NR^(a)CH₂CH═CHCONR^(a) ₂, (CH₂)_(m)-tetrazole, O(CH₂)_(n)-tetrazole,O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, and SO₂NHCH₃;

the other of X, Y, X′, Y′, X″, and Y″ are independently selected from:H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, NO₂, and NR₂;

R is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl;

R^(a) is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl;

Z is selected from: H, C₁₋₄ alkyl, OH, O—C₁₋₄ alkyl, acetyloxy, andpropionyloxy;

Q is selected from: is selected from H, C₁₋₄ alkyl, (CH₂CH₂O)_(p)R,(CH₂)_(n)-heteroaryl, and (CH₂)_(m)-aryl, wherein the heteroaryl andaryl are substituted with 0-3 groups selected from H, C₁₋₄ alkyl,halogen, CF₃, O—C₁₋₄ alkyl, and NO₂;

M is C═O or SO₂;

p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

m is independently selected from 0, 1, 2, and 3; and,

n is independently selected from 1, 2, and 3.

[3] In another embodiment, the present invention provides novelcompounds of formula I or a stereoisomer or pharmaceutically acceptablesalt thereof, wherein:

X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C₁₋₄ alkyl,halogen, CF₃, O—C₁₋₄ alkyl, NO₂, O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R,and NR₂;

Z is selected from: O(CH₂CH₂O)_(p)R, O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R,O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)CONH₂, O(CH₂)_(n)C(NH)NH₂, OCH₂CH═CHCONH₂,O(CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, andO(CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole;

Q is selected from: H, C₁₋₄ alkyl, (CH₂CH₂O)_(p)R, (CH₂)_(n)-heteroaryl,and (CH₂)_(n)-aryl, wherein the heteroaryl and aryl are substituted with0-3 groups selected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, andNO₂;

M is C═O or SO₂;

R is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl;

p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

m is independently selected from 0, 1, 2, and 3; and,

n is independently selected from 1, 2, and 3.

[4] In another embodiment, the present invention provides novelcompounds of formula I or a stereoisomer or pharmaceutically acceptablesalt thereof, wherein:

X, Y, X′, Y′, X″, and Y″ are individually selected from the following:H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, NO₂, O(CH₂CH₂O)_(p)R,NR^(a)(CH₂CH₂O)_(p)R, and NR₂;

Z is selected from: H, C₁₋₄ alkyl, OH, O—C₁₋₄ alkyl, acetyloxy, andpropionyloxy;

Q is selected from: —(CH₂)_(n)-tetrazole, —CHA(CH₂)_(m)C(O)NHR,CHA(CH₂)_(m)CO₂R, (CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R,(CH₂)_(n)-phenyl-(CH₂)_(m)CONH₂, (CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole,and (CH₂CH₂O)_(p)R;

M is C═O or SO₂;

A is selected from H, C₁₋₄ alkyl, (CH₂)_(m)—C₃₋₆-cycloalkyl, CH₂OH,CH(CH₃)OH, (CH₂)_(m)-phenyl, wherein the phenyl is substituted with 0-3groups selected from H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, and NO₂;

R is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl;

p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;

m is independently selected from 0, 1, 2, and 3; and,

n is independently selected from 1, 2, and 3.

In another embodiment, the present invention provides novelpharmaceutical compositions, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method fortreating a disease, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt form thereof, whereinthe disease is selected from obesity, diabetes, cardiometabolicdisorders, and a combination thereof.

In another embodiment, the diabetes disorder is selected from Type 1diabetes, Type 2 diabetes, inadequate glucose tolerance, and insulinresistance.

In another embodiment, the cardiometabolic disorder is selected fromdyslipidemias (e.g., elevated levels of triglycerides, elevated levelsof low-density lipoprotein (“bad” cholesterol), or low levels ofhigh-density lipoprotein (“good” cholesterol”)) and hypertension.

In another embodiment, the present invention provides a novel method fortreating a co-morbidity of obesity, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundof the present invention or a pharmaceutically acceptable salt formthereof.

In another embodiment, the co-morbidity is selected from diabetes,Metabolic Syndrome, dementia, and heart disease.

In another embodiment, the co-morbidity is selected from hypertension;gallbladder disease; gastrointestinal disorders; menstrualirregularities; degenerative arthritis; venous statis ulcers; pulmonaryhypoventilation syndrome; sleep apnea; snoring; coronary artery disease;arterial sclerotic disease; pseudotumor cerebri; accident proneness;increased risks with surgeries; osteoarthritis; high cholesterol; and,increased incidence of malignancies of the ovaries, cervix, uterus,breasts, prostrate, and gallbladder.

In another embodiment, the present invention also provides a method ofpreventing or reversing the deposition of adipose tissue in a mammal bythe administration of a compound of the present invention. By preventingor reversing the deposition of adipose tissue, compound of the presentinvention are expected to reduce the incidence or severity of obesity,thereby reducing the incidence or severity of associated co-morbidities.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides the use ofcompounds of the present invention for the manufacture of a medicamentfor the treatment of obesity, diabetes, cardiometabolic disorders, and acombination thereof.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of aspects of the invention notedherein. It is understood that any and all embodiments of the presentinvention may be taken in conjunction with any other embodiment orembodiments to describe additional embodiments. It is also to beunderstood that each individual element of the embodiments is intendedto be taken individually as its own independent embodiment. Furthermore,any element of an embodiment is meant to be combined with any and allother elements from any embodiment to describe an additional embodiment.

The examples provided in the definitions present in this application arenon-inclusive unless otherwise stated. They include but are not limitedto the recited examples.

The compounds herein described may have asymmetric centers, geometriccenters (e.g., double bond), or both. All chiral, diastereomeric,racemic forms and all geometric isomeric forms of a structure areintended, unless the specific stereochemistry or isomeric form isspecifically indicated. Compounds of the present invention containing anasymmetrically substituted atom may be isolated in optically active orracemic forms. It is well known in the art how to prepare opticallyactive forms, such as by resolution of racemic forms, by synthesis fromoptically active starting materials, or through use of chiralauxiliaries. Geometric isomers of olefins, C═N double bonds, or othertypes of double bonds may be present in the compounds described herein,and all such stable isomers are included in the present invention.Specifically, cis and trans geometric isomers of the compounds of thepresent invention may also exist and may be isolated as a mixture ofisomers or as separated isomeric forms. All processes used to preparecompounds of the present invention and intermediates made therein areconsidered to be part of the present invention. All tautomers of shownor described compounds are also considered to be part of the presentinvention.

“Alkyl” includes both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms. C₁₋₆alkyl, for example, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups.Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, and s-pentyl.

“Alkenyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more unsaturatedcarbon-carbon bonds that may occur in any stable point along the chain,such as ethenyl and propenyl. C₂₋₆ alkenyl includes C₂, C₃, C₄, C₅, andC₆ alkenyl groups.

“Alkynyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more triple carbon-carbonbonds that may occur in any stable point along the chain, such asethynyl and propynyl. C₂₋₆ Alkynyl includes C₂, C₃, C₄, C₅, and C₆alkynyl groups.

“Cycloalkyl” includes the specified number of hydrocarbon atoms in asaturated ring, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. C₃₋₈ cycloalkyl includes C₃,C₄, C₅, C₆, C₇, and C₈ cycloalkyl groups.

“Cyclic amine” is a hydrocarbon ring wherein one carbon atom of the ringhas been replaced by a nitrogen atom. The cyclic amine can beunsaturated, partially saturated, or fully saturated. The cyclic aminecan also be bicyclic, tricyclic, and polycyclic. Examples of cyclicamine include pyrrolidine and piperidine.

Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

“Counterion” is used to represent a small, negatively charged species,such as chloride, bromide, hydroxide, acetate, and sulfate.

The group “C₆H₄” represents a phenylene.

“Aryl” refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 memberedmonocyclic, bicyclic, or tricyclic ring, wherein at least one ring, ifmore than one is present, is aromatic. Examples of aryl includefluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

“Heteroaryl” refers to any stable 5, 6, 7, 8, 9, 10, 11, or 12 memberedmonocyclic, bicyclic, or tricyclic heterocyclic ring that is aromatic,and which consists of carbon atoms and 1, 2, 3, or 4 heteroatomsindependently selected from the group consisting of N, O, and S. If theheteroaryl group is bicyclic or tricyclic, then at least one of the twoor three rings must contain a heteroatom, though both or all three mayeach contain one or more heteroatoms. If the heteroaryl group isbicyclic or tricyclic, then only one of the rings must be aromatic. TheN group may be N, NH, or N-substituent, depending on the chosen ring andif substituents are recited. The nitrogen and sulfur heteroatoms mayoptionally be oxidized (e.g., S, S(O), S(O)₂, and N—O). The heteroarylring may be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure. The heteroaryl rings describedherein may be substituted on carbon or on a nitrogen atom if theresulting compound is stable.

Examples of heteroaryl includes acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolyl,1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

“Mammal” and “patient” cover warm blooded mammals that are typicallyunder medical care (e.g., humans and domesticated animals). Examplesinclude feline, canine, equine, bovine, and human, as well as justhuman.

“Treating” or “treatment” covers the treatment of a disease-state in amammal, and includes: (a) preventing the disease-state from occurring ina mammal, in particular, when such mammal is predisposed to thedisease-state but has not yet been diagnosed as having it; (b)inhibiting the disease-state, i.e., arresting it development; and/or (c)relieving the disease-state, i.e., causing regression of the diseasestate until a desired endpoint is reached.

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic,ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric,edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic,hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic,hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic,pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,propionic, salicyclic, stearic, subacetic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare useful. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,1990, p 1445, the disclosure of which is hereby incorporated byreference.

“Therapeutically effective amount” includes an amount of a compound ofthe present invention that is effective when administered alone or incombination to treat obesity or another indication listed herein.“Therapeutically effective amount” also includes an amount of thecombination of compounds claimed that is effective to treat the desiredindication. The combination of compounds can be a synergisticcombination. Synergy, as described, for example, by Chou and Talalay,Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect of thecompounds when administered in combination is greater than the additiveeffect of the compounds when administered alone as a single agent. Ingeneral, a synergistic effect is most clearly demonstrated atsub-optimal concentrations of the compounds. Synergy can be in terms oflower cytotoxicity, increased effect, or some other beneficial effect ofthe combination compared with the individual components.

Obesity is defined as having a body mass index (BMI) of 30 or above. Theindex is a measure of an individual's body weight relative to height.BMI is calculated by dividing body weight (in kilograms) by height (inmeters) squared. Normal and healthy body weight is defined as having aBMI between 20 and 24.9. Overweight is defined as having a BMI≧25.Obesity has reached epidemic proportions in the U.S., with 44 millionobese Americans, and an additional eighty million deemed medicallyoverweight.

Obesity is a disease characterized as a condition resulting from theexcess accumulation of adipose tissue, especially adipose tissuelocalized in the abdominal area. It is desirable to treat overweight orobese patients by reducing their amount of adipose tissue, and therebyreducing their overall body weight to within the normal range for theirsex and height. In this way, their risk for co-morbidities such asdiabetes and cardiovascular disease will be reduced. It is alsodesirable to prevent normal weight individuals from accumulatingadditional, excess adipose tissue, effectively maintaining their bodyweights at a BMI<25, and preventing the development of co-morbidities.It is also desirable to control obesity, effectively preventingoverweight and obese individuals from accumulating additional, excessadipose tissue, reducing the risk of further exacerbating theirco-morbidities.

Cannabinoid receptors are located in a number of peripheral (non-CNS)tissues, including thyroid gland, adrenal gland, reproductive organs,adipose tissue, liver, muscle, and gastrointestinal tract. Cannabinoidreceptor antagonists/invers agonists being developed to treat obesityand smoking cessation, regardless of route of administration, enter theCNS from the systemic circulation. While present in the systemiccirculation, such drugs have access to peripheral tissues. One of skillin the art recognizes that cannabinoid receptor antagonists intended toenter the CNS from the systemic circulation in order to treat obesityand smoking cessation, also have access to cannabinoid receptors inperipheral tissues. Thus, a cannabinoid receptor antagonist useful forthe present invention may have some access to the CNS from the systemiccirculation.

Drugs enter the CNS from the systemic circulation by crossing theblood-brain barrier (BBB). The BBB is a highly specialized ‘gate-keeper’that protects the brain by preventing the entry of many potentiallyharmful substances into the CNS from the systemic circulation. Much isknown about the BBB, and of the physical-chemical properties requiredfor compounds transported across it.

Drugs that do not cross the BBB into the CNS or that are readilyeliminated through transport mechanisms (J Clin Invest. 97, 2517 (1996))are known in the literature and have low CNS activity due to theirinability to develop brain levels necessary for pharmacological action.The BBB has at least one mechanism to remove drugs prior to theiraccumulation in the CNS. P-Glycoproteins (P-gp) localized in plasmamembrane of the BBB can influence the brain penetration andpharmacological activity of many drugs through translocation acrossmembranes. The lack of accumulation into the brain by some drugs can beexplained by their active removal from the brain by P-gp residing in theBBB. For example, the typical opioid drug loperamide, clinically used asan antidiarrheal, is actively removed from the brain by P-gp, thusexplaining its lack of opiate-like CNS effects. Another example isdomperidone, a dopamine receptor blocker that participates in the P-gptransport (J Clin Invest. 97, 2517 (1996)). Whereas dopamine receptorblockers that cross the BBB can be used to treat schizophrenia, thereadily-eliminated domperidone can be used to prevent emesis, withoutthe likelihood of producing adverse CNS effects.

In addition to the above compounds, agents possessing structuralcharacteristics that retard or prevent BBB penetration or contribute toparticipation in active elimination processes have been identified invarious classes of therapeutics. These include antihistamines (DrugMetab. Dispos. 31, 312 (2003)), beta-adrenergic receptor antagonists(B-blockers)(Eur. J. Clin. Pharmacol. 28, Suppl: 21-3 (1985); Br. J.Clin. Pharmacol, 11 (6), 549-553 (1981)), non-nucleoside reversetranscriptase inhibitors (NNRTIs)(J. Pharm Sci., 88(10) 950-954 (1999)),and opioid antagonists. This latter group has been tested in relation totheir activity in the GI tract. These peripherally selective opioidantagonists are described in various US patents as being useful in thetreatment of non-CNS pathologies in mammals, in particular those of theGI tract (see U.S. Pat. No. 5,260,542; U.S. Pat. No. 5,434,171; U.S.Pat. No. 5,159,081; and U.S. Pat. No. 5,270,238).

Other types of non-brain penetrant compounds can be prepared through thecreation of a charge within the molecule. Thus, the addition of a methylgroup to the tertiary amine functionality of the drugs scopolamine oratropine, unlike the parent molecules, prevents their passage across theBBB through the presence of a positive charge. However, the newmolecules (methyl-scopolamine and methyl-atropine) retain their fullanticholinergic pharmacological properties. As such, these drugs canalso be used to treat peripheral diseases, without the concern ofadverse CNS effects. The quaternary ammonium compound methylnaltrexoneis also used for the prevention and/or treatment of opioid andnon-opioid induced side effects associated with opioid administration.

The discovery that the anti-obesity and anti-diabetic activity ofcannabinoid receptor antagonists may in part be mediated by a non-CNSmechanism could make it beneficial for the compounds of the presentinvention to be peripherally restricted, i.e., have an inability orlimited ability to cross the BBB, or be readily eliminated from thebrain through active transport systems. It may be desirable for thecompounds of the present invention to be peripherally restricted, whichin turn will result in no or very limited CNS effects. Compounds thatprovide peripherally mediated anti-obesity properties should result intherapeutic agents with greater safety, as previously demonstrated inearlier classes of peripherally restricted agents. It can be desirablethat the compounds of the present invention, when administered in atherapeutically effective amount, have no or very limited CNS effects.It can also be desirable that the lack of CNS effects is a result of thecompounds of the present invention having minimal brain concentrationswhen administered in therapeutically effective amounts. In this context,minimal brain concentrations means levels that are too low to betherapeutically effective for the treatment of a CNS indication or toolow to cause significant or measurable deleterious or undesired sideeffects.

SLV319 (Compound I when X and X″ are 4-Cl; X′, Y, Y′, Y″, and Z are H; Qis CH₃; and M is SO₂) is a drug that crosses the BBB and is indicatedfor the treatment of obesity. It is believed that SLV319 works to treatobesity via a CNS mechanism. Compounds like SLV319 and compound AA havebeen described in various publications including J. Med. Chem. 2004,47(3), 627 and U.S. Pat. No. 6,476,060. In compound AA, one of X, Y, X′,Y′, X″, Y, Z or Q is a group capable of reducing or limiting the CNSactivity of compound AA. This reduced or limited CNS activity occurs viaat least one of X, Y, X′, Y′, X″, Y, Z and Q being a group that eitherlimits compound AA's ability to cross the BBB relative to that of SLV319or enables it to be actively removed from the brain at a rate greaterthan that of SLV319. Examples of the amount of compound AA present inthe brain can include (a) from 50, 55, 60, 65, 70, 75, 80, 85, 90, 91,92, 93, 94, 95, 96, 97, 98, 99, to 100% lower than SLV319, (b) from 90,91, 92, 93, 94, 95, 96, 97, 98, 99, to 100% lower than SLV319, and (c)from 98, 99, to 100% lower than SLV319, when administered at the samedosage.

The compounds of the present invention are expected to be cannabinoidreceptor antagonists or inverse agonists.

An inverse agonist is a compound that not only blocks the action of theendogenous agonist at the receptor, but also exhibits its own activity,which is usually the opposite of that shown by the agonist. Inverseagonists are also effective against certain types of receptors (e.g.,certain histamine receptors/GABA receptors), which have intrinsicactivity without the interaction of a ligand upon them (also referred toas ‘constitutive activity’).

Most methods of treating obesity are dependent on a significantreduction in energy intake, either by a decrease in food intake (e.g.,sibutramine) or by inhibition of fat absorption (e.g., orlistat). In thepresent invention, it can be desirable for adipose tissue to besignificantly reduced in the absence of a significant reduction in foodintake. The weight loss, as a result of the present invention, comesfrom the treatment with a CB1 antagonist, largely independent ofappetite and food intake. Examples of the level of food intake duringadipose tissue loss include (a) food intake is maintained, increased orabout 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 20% below the normal range of the subject prior to being treatedin accordance with the present invention (i.e., its pre-administrationlevel); (b) food intake is maintained, increased, or about 0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below itspre-administration level; (c) food intake is maintained, increased orabout 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below its pre-administrationlevel; and (d) food intake level is maintained, increased or about 0, 1,2, 3, 4, or 5% below its pre-administration level.

In some cases, loss of adipose tissue can be accompanied by aconcomitant loss of lean muscle mass. This is particularly evident incancer patients who show a wasting of all body tissue components,including adipose tissue and lean muscle mass. In the present invention,however, it can be desirable for body fat to be significantly reduced inthe absence of a significant reduction in lean body mass. Adipose tissueloss comes from treatment with a CB1 antagonist, independent of asignificant change in lean body mass. Examples of the level of lean bodymass during adipose tissue loss include (a) lean body mass ismaintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, or 30% below the normal range of the subject prior to beingtreated in accordance with the present invention (i.e., itspre-administration level); (b) lean body mass is maintained, increased,or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,or 15% below pre-administration levels; (c) lean body mass ismaintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8,9, or 10% below pre-administration levels; and (d) lean body mass ismaintained, increased, or is no more than about 1, 2, 3, 4, or 5% belowpre-administration levels.

In some cases, loss of adipose tissue can be accompanied by aconcomitant loss of water mass. This is particularly evident with dietregimens that promote dehydration. In the present invention, it can bedesirable for body fat to be significantly reduced in the absence of asignificant reduction in water mass. In other words, adipose tissue losscomes from treatment with a CB1 antagonist, independent of a significantchange in water mass. Examples of the level of water mass during adiposetissue loss include (a) water mass is maintained, increased, or is nomore than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% below thenormal range of the subject prior to being treated in accordance withthe present invention (i.e., its pre-administration level); (b) watermass is maintained, increased, or is no more than about 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below pre-administration levels;(c) water mass is maintained, increased, or is no more than about 1, 2,3, 4, 5, 6, 7, 8, 9, or 10% below pre-administration levels; and (d)water mass is maintained, increased, or is no more than about 1, 2, 3,4, or 5% below pre-administration levels.

Sibutramine and orlistat are currently marketed for use in the treatmentof obesity. These two compounds achieve weight loss through entirelydifferent mechanisms. Sibutramine, a CNS appetite suppressant, inhibitsthe neuronal reuptake of serotonin and noradrenaline. Orlistat inhibitsgut lipase enzymes that are responsible for breaking down ingested fat.

Cannabinoid receptor antagonists/inverse agonists can promote weightloss through inhibition of peripheral cannabinoid receptors, as well asmechanisms entirely different from appetite suppressants, gut lipaseinhibitors, and other agents with similar indications (e.g., serotoninagonists, leptin, fatty acid synthase inhibitors, monoamine oxidase(MAO) inhibitors). Co-administration of a cannabinoid receptorantagonist/inverse agonist together with one or more other agents thatare useful for treating the indications described above (e.g., obesity,diabetes, cardiometabolic disorders, and a combination thereof) isexpected to be beneficial, by producing, for example, either additive orsynergistic effects. Examples of additional agents include an appetitesuppressant, a lipase inhibitor, and a MAO inhibitor (e.g., MAO-B, and acombination of MAO-A/B). Therefore, the present invention provides amethod of treating obesity, diabetes, and/or cardiometabolic disorders,comprising administering a therapeutically effective amount of acompound of the present invention and a second component effective fortreating the desired indication.

Examples of second components include anti-obesity agents, whichinclude, but are not limited to: 1) growth hormone secretagogues; 2)growth hormone secretagogue receptor agonists/antagonists; 3)melanocortin agonists; 4) Mc4r (melanocortin 4 receptor) agonists;5).beta.-3 agonists; 7) 5HT2C (serotonin receptor 2C) agonists; 8)orexin antagonists; 9) melanin concentrating hormone antagonists; 10)melanin-concentrating hormone 1 receptor (MCH1R) antagonists; 11)melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists;12) galanin antagonists; 13) CCK agonists; 14) CCK-A (cholecystokinin-A)agonists; 16) corticotropin-releasing hormone agonists; 17) NPY 5antagonists; 18) NPY 1 antagonists; 19) histamine receptor-3 (H3)modulators; 20) histamine receptor-3 (H3) antagonists/inverse agonists;21)_(n)(3-hydroxy steroid dehydrogenase-1 inhibitors (.beta.-HSD-1); 22)PDE (phosphodiesterase) inhibitors; 23) phosphodiesterase-3B (PDE3B)inhibitors; 24) NE (norepinephrine) transport inhibitors; 25)non-selective serotonin/norepinephrine transport inhibitors, such assibutramine, phentermine, or fenfluramine; 26) ghrelin antagonists; 28)leptin derivatives; 29) BRS3 (bombesin receptor subtype 3) agonists; 30)CNTF (Ciliary neurotrophic factors); 31) CNTF derivatives, such asaxokine (Regeneron); 32) monoamine reuptake inhibitors; 33) UCP-1(uncoupling protein-1), 2, or 3 activators; 34) thyroid hormone .beta.agonists; 35) FAS (fatty acid synthase) inhibitors; 37) DGAT2(diacylglycerol acyltransferase 2) inhibitors; 38) ACC2 (acetyl-CoAcarboxylase-2) inhibitors; 39) glucocorticoid antagonists; 40)acyl-estrogens; 41) lipase inhibitors, such as orlistat (Xenical®); 42)fatty acid transporter inhibitors; 43) dicarboxylate transporterinhibitors; 44) glucose transporter inhibitors; 45) phosphatetransporter inhibitors; 46) serotonin reuptake inhibitors; 47) Metformin(Glucophage®); 48) Topiramate (Topimax®); and/or 49) MAO inhibitors.

Examples of MAO inhibitors include Moclobemide; Brofaromine; BW A616U;Ro 41-1049; RS-2232; SR 95191; Harmaline; Harman; Amiflamine; BW1370U87; FLA 688; FLA 788; Bifemelane; Clorgyline; LY 51641; MDL 72,394;544-Benzyloxyphenyl)-3-(2-cyanoethyl)-(3H)-1,3,4-oxadiazol-2-one;5-(4-Arylmethoxyphenyl)-2-(2-cyanoethyl)tetrazoles; Lazabemide; Ro16-6491; Almoxatone; XB308; RS-1636; RS-1653; NW-1015; SL 340026;L-selegiline; Rasagiline; Pargyline; AGN 1135; MDL 72,974; MDL 72,145;MDL 72,638; LY 54761; MD 780236; MD 240931; Bifemelane; Toloxatone;Cimoxatone; Iproniazid; Phenelzine; Nialamide; Phenylhydrazine;1-Phenylcyclopropylamine; Isocarboxazid; and, Tranylcypromine.Additional examples of MAO inhibitors can be found in U.S. A No.60/696,067; U.S. A No. 60/686,585; U.S. A No. 60/698,867; and U.S. A No.60/704,679, the contents of which are incorporated herein by reference.

Examples of second components useful for treating diabetes include (a)insulin sensitizers including (i) PPAR-γ agonists such as the glitazones(e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone),and compounds disclosed in WO97/27857, 97/28115, 97/28137, and 97/27847;and (ii) biguanides such as metformin and phenformin; (b) insulin orinsulin mimetics; (c) sulfonylureas such as tolbutamide and glipizide,or related materials; (d) α-glucosidase inhibitors (e.g., acarbose); (e)cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,rivastatin, and other statins), (ii) sequestrants (e.g., cholestyramine,colestipol, and dialkylaminoalkyl derivatives of a cross-linkeddextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof,(iv) PPAR-α agonists (e.g., fenofibric acid derivatives includinggemfibrozil, clofibrate, fenofibrate, and bezafibrate), (v) inhibitorsof cholesterol absorption (e.g., β-sitosterol) and acyl CoA: cholesterolacyltransferase inhibitors (e.g., melinamide), and (vi) probucol; (f)PPAR-α/γ agonists; (g) antiobesity compounds (described previously); (h)ileal bile acid transporter inhibitors; and (i) insulin receptoractivators.

The compounds of the present invention are expected to be CB1 receptorinhibitors/inverse agonists and are expected to be useful for treatingdiseases mediated by the CB₁ receptor. The compounds of the present areexpected to possess an affinity in vitro for the central and/orperipheral cannabinoid receptors under the experimental conditionsdescribed by Devane et al., Molecular Pharmacology, 1988, 34, 605-613.The compounds according to the invention are also expected to possess anaffinity for the cannabinoid receptors present on preparations ofelectrically stimulated isolated organs. These tests can be performed onguinea-pig ileum and on mouse vas deferens according to Roselt et al.,Acta Physiologica Scandinavia 1975, 94, 142-144, and according toNicolau et al., Arch. Int. Pharmacodyn, 1978, 236, 131-136.

CB1 receptor affinities can be determined using membrane preparations ofChinese hamster ovary (CHO) cells in which the human cannabinoid CB1receptor is stably transfected (Biochem J. 1991, 279, 129-134) inconjunction with [3H]CP-55,940 as radioligand. After incubation of afreshly prepared cell membrane preparation with the [3H]-radioligand,with or without addition of test compound, separation of bound and freeligand is performed by filtration over glass fiber filters.Radioactivity on the filter is measured by liquid scintillationcounting. The IC₅₀ values can be determined from at least threeindependent measurements.

In the present invention, the compound(s) of the present invention canbe administered in any convenient manner (e.g., enterally orparenterally). Examples of methods of administration include orally andtransdermally. One skilled in this art is aware that the routes ofadministering the compounds of the present invention may varysignificantly. In addition to other oral administrations, sustainedrelease compositions may be favored. Other acceptable routes may includeinjections (e.g., intravenous, intramuscular, subcutaneous, andintraperitoneal); subdermal implants; and, buccal, sublingual, topical,rectal, vaginal, and intranasal administrations. Bioerodible,non-bioerodible, biodegradable, and non-biodegradable systems ofadministration may also be used. Examples of oral formulations includetablets, coated tablets, hard and soft gelatin capsules, solutions,emulsions, and suspensions.

If a solid composition in the form of tablets is prepared, the mainactive ingredient can be mixed with a pharmaceutical vehicle, examplesof which include silica, starch, lactose, magnesium stearate, and talc.The tablets can be coated with sucrose or another appropriate substanceor they can be treated so as to have a sustained or delayed activity andso as to release a predetermined amount of active ingredientcontinuously. Gelatin capsules can be obtained by mixing the activeingredient with a diluent and incorporating the resulting mixture intosoft or hard gelatin capsules. A syrup or elixir can contain the activeingredient in conjunction with a sweetener, which is preferablycalorie-free, an antiseptic (e.g., methylparaben and/or propylparaben),a flavoring, and an appropriate color. Water-dispersible powders orgranules can contain the active ingredient mixed with dispersants orwetting agents or with suspending agents such as polyvinylpyrrolidone,as well as with sweeteners or taste correctors. Rectal administrationcan be effected using suppositories, which are prepared with bindersmelting at the rectal temperature (e.g., cocoa butter and/orpolyethylene glycols). Parenteral administration can be effected usingaqueous suspensions, isotonic saline solutions, or injectable sterilesolutions, which contain pharmacologically compatible dispersants and/orwetting agents (e.g., propylene glycol and/or polyethylene glycol). Theactive ingredient can also be formulated as microcapsules ormicrospheres, optionally with one or more carriers or additives. Theactive ingredient can also be presented in the form of a complex with acyclodextrin, for example α-, β-, or γ-cyclodextrin,2-hydroxypropyl-β-cyclodextrin, and/or methyl-β-cyclodextrin.

The dose of the compound of the present invention administered dailywill vary on an individual basis and to some extent may be determined bythe severity of the disease being treated (e.g., obesity, diabetes, andcardiometabolic disorders). The dose of the compound of the presentinvention will also vary depending on the compound administered.Examples of dosages of compounds of the present invention include fromabout 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15,20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 76, 80, 85, 90, 95, to 100mg/kg of mammal body weight. The compound can be administered in asingle dose or in a number of smaller doses over a period of time. Thelength of time during which the compound is administered varies on anindividual basis, and can continue until the desired results areachieved (i.e., reduction of body fat, prevention of a gain in body fat,reduced glucose levels, improved insulin sensitivity). Therapy could,therefore, last from 1 day to weeks, months, or even years dependingupon the subject being treated, the desired results, and how quickly thesubject responds to treatment in accordance with the present invention.

A possible example of a tablet of the present invention is as follows.

Ingredient mg/Tablet Active ingredient 100 Powdered lactose 95 Whitecorn starch 35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10Magnesium stearate 2 Tablet weight 250

A possible example of a capsule of the present invention is as follows.

Ingredient mg/Tablet Active ingredient 50 Crystalline lactose 60Microcrystalline cellullose 34 Talc 5 Magnesium stearate 1 Capsule fillweight 150

In the above capsule, the active ingredient has a suitable particlesize. The crystalline lactose and the microcrystalline cellulose arehomogeneously mixed with one another, sieved, and thereafter the talcand magnesium stearate are admixed. The final mixture is filled intohard gelatin capsules of suitable size.

A possible example of an injection solution of the present invention isas follows.

Ingredient mg/Tablet Active substance 1.0 mg 1 N HCl 20.0 μl acetic acid0.5 mg NaCl 8.0 mg Phenol 10.0 mg 1 N NaOH q.s. ad pH 5 H₂O q.s. ad 1 mL

Synthesis

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis (e.g., seeU.S. Pat. No. 6,476,060 B2, J Med Chem 2004, 47, 627). The compounds ofthe present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).All references cited herein are hereby incorporated in their entiretyherein by reference.

Scheme 1 shows how to convert 2′-, 3′-, or4′-(carbo-t-butoxymethoxy)-2-phenylacetophenones, prepared fromcommercially available 2′-, 3′- or 4′-methoxy-2-phenylacetophenones viaO-demethylation using HBr/HOAc or BBr₃/CH₂Cl₂ and alkylation of theresultant phenol with t-butyl bromoacetate in the presence of base, in37% aqueous formaldehyde containing piperidine under reflux to thecorresponding acrylophenones (step a). Treatment of the acrylophenoneswith hydrazine hydrate in ethanol can produce the 3,4-diarylpyrazolines(step b). The diarylpyrazolines can be further treated witharylsulfonyldithioimidocarbonic acid methyl esters, prepared from thecorresponding aryl sulfonamides, CS₂ and MeI (see J. Med. Chem., 47, 627(2004); Chem. Ber. 1966, 99, 2885), in a solvent (e.g., acetonitrile) inthe presence of triethylamine at reflux to yield thepyrazole-1-carboximidothioic acid methyl ester (step c). Furtherexposure of these iminothioethers to an aqueous solution of methylamineand methylene chloride at room temperature should afford thepyrazoline-1-carboxamidines (step d). Hydrolysis of the ester usingTFA/CH₂Cl₂ should produce the carboxylic acid (step e).

Scheme 2 describes how 2-(2′-, 3′- or4′-carbo-t-butoxymethoxyphenyl)acetophenones (prepared similarly toscheme 1) should provide the corresponding acrylophenones (step a).Treatment of the acrylophenones with hydrazine hydrate in ethanol canproduce the 3,4-diarylpyrazolines (step b). The diarylpyrazolines can befurther treated with arylsulfonyldithioimidocarbonic acid methyl estersin a solvent like acetonitrile in the presence of triethylamine atreflux to yield pyrazole-1-carboximidothioic acid methyl esters (stepc). Further exposure of these iminothioethers to an aqueous solution ofmethylamine and methylene chloride at room temperature should afford thepyrazoline-1-carboxamidines (step d). Hydrolysis of the ester usingTFA/CH₂Cl₂ should produce the carboxylic acid (step e).

Scheme 3 shows the conversion of 4′-chloro-2-phenylacetophenone in 37%aqueous formalin and MeOH containing piperidine and acetic acid atreflux that should occur affording the acrylophenone (J. Agric. FoodChem. 1979, 27(2), 406)_(n)(step a). Treatment of the acrylophenone withhydrazine hydrate in ethanol can produce the 3,4-diarylpyrazolines (stepb). The diarylpyrazolines can be further treated witharylsulfonyldithioimidocarbonic acid methyl esters in a solvent likeacetonitrile in the presence of triethylamine at reflux to yield thepyrazole-1-carboximidothioic acid methyl ester (step c). Furtherexposure of these iminothioethers to beta-alanine t-butyl ester inethanol and methylene chloride containing triethylamine should yield thepyrazoline-esters (step d). Hydrolysis of the ester using TFA/CH₂Cl₂should produce the carboxylic acid (step e). Treatment of the ester withanhydrous ammonia in methanol at about 0° to room temperature can affordthe carboxamido compound (step f). Alternatively, the iminothioetherscan be coupled with other amino acid esters to give adducts (step g)that can be hydrolyzed to the carboxylic acids (step h). These acids maybe converted to the carboxamides using oxalyl chloride in dichloroethanefollowed by anhydrous ammonia, or Boc₂O in pyridine/THF followed byanhydrous ammonia (step i).

Scheme 4 illustrates how oxidation of 4′-chloro-2-phenylacrylophenone inmethylene chloride with m-chloroperbenzoic acid should provide theepoxide (step a), which upon treatment with hydrazine hydrate in ethanolsolution at about 35-40° C. can give the 3,4-diarylpyrazoline alcohol(step b). The pyrazoline can be protected using di-t-butyl-dicarbonate(t-Boc anhydride) in the presence of a base to give theN-t-BOC-pyrazoline (step c). The carbamate alcohol can then bedeprotonated with sodium hydride in a solvent like DMF followed byalkylation with ethyl 4-bromocrotonate to yield the ester (step d).Removal of the t-BOC group can be achieved via treatment with TFA (stepe). The pyrazoline can then be reacted witharylsulfonyldithioimidocarbonic acid methyl esters in a solvent likeacetonitrile in the presence of triethylamine at reflux to yield thepyrazole-1-carboximidothioic acid methyl ether (step f). Furtherexposure of these iminothioethers to an aqueous solution of methylamineand methylene chloride at room temperature can afford thepyrazoline-1-carboxamidines (step g), and hydrolysis of the ester usingLiOH in aqueous THF solution can produce the carboxylic acid (step h).The carboxamides can be prepared by treatment of the ester withanhydrous ammonia in alcohol at −20° C. to ambient temperature (step i).

Scheme 5 shows how heating a solution of the 3,4-diarylpyrazoline andS-methylisothiourea in pyridine can form the pyrazoline-1-carboxamidine(step a). Treatment of this amidine with t4-cyanobenzenesulfonylchloride in acetonitrile in the presence of N,N-dimethyl-4-aminopyridineand triethylamine can give the carboxamidine-coupled sulfonamidederivative (step b). Conversion of the nitrile to thephenylcarboxamidine can be accomplished using HCl (gas) in MeOH at 0° C.to room temperature, followed by ammonium carbonate or anhydrous ammoniain MeOH at about 0° C. to room temperature (step c).

Scheme 6 describes how the reaction of a freshly prepared anhydrousacetonitrile solution of 4-chlorobenzoylisothiocyanate, made from4-chlorobenzoylchloride and ammonium isocyanate (see J. Heterocycl.Chem. 1991, 28, 1645), and a 3,4-diarylpyrazoline stirred in the coldcan afford the pyrazoline—adduct (step a). Treatment of thisthiocarboxamide with amino compounds such as ethyl beta-alanine in thepresence of HgCl₂ can produce the benzoyl guanidines (step b).Hydrolysis of the ester using LiOH in aqueous THF solution can producethe carboxylic acid (step c). Further conversion of the acid to the acidchloride followed by treatment with anhydrous ammonia should afford thecarboxamide (step d).

Scheme 7 depicts how condensation of a solution of4′-nitro-2-phenylacetophenone in 37% aqueous formalin and MeOHcontaining piperidine and acetic acid should afford after heating atreflux, the corresponding acrylophenone (step a). Treatment of theacrylophenone with hydrazine hydrate in ethanol can produce the3,4-diarylpyrazoline (step b). The pyrazoline can then be reacted witharylsulfonyldithioimidocarbonic acid methyl esters in a solvent likeacetonitrile in the presence of triethylamine at reflux to yield thecorresponding pyrazole-1-carboximidothioic acid methyl ester (step c).The nitro group can be reduced using sodium dithionite in aqueous basicsolution to produce the aniline compound (step d). Acylation of theaniline with ethyl malonyl chloride in the presence of base shouldproduce the amide (step e). Treatment of the amidoester with amines suchas methylamine or anhydrous ammonia in a solvent such as methanol ormethylene chloride at zero degrees to room temperature should afford thepyrazole-1-carboxamidines with the terminal carboxamido group (step f).Alternatively, the aniline compound can be treated with methanesulfonylchloride to give the sulfonamide (step g), which upon exposure to anaqueous solution of methylamine and methylene chloride at roomtemperature should afford the pyrazoline-1-carboxamidines (step h).

Scheme 8 illustrates how treatment of 4′-cyano-2-phenylacrylophenonewith hydrazine hydrate in ethanol will produce the 3,4-diarylpyrazoline(step a). The pyrazoline can then be reacted with tri-n-butyltin azide,conveniently prepared in situ by the reaction of one equivalent ofsodium azide and one equivalent of tri-n-butyltin chloride (see J. Med.Chem. 1991, 56, 2395), in reluxing toluene or xylene to afford thetri-n-butyltin-tetrazole adduct (step b). The tri-n-butyltin-adduct canbe converted to the trityl-tetrazole adduct by treatment with oneequivalent of aqueous sodium hydroxide solution and one equivalent oftrityl chloride at room temperature (step c). Reaction of this adductwith arylsulfonyldithioimidocarbonic acid methyl esters in a solventlike acetonitrile in the presence of triethylamine at reflux shouldyield the pyrazole-1-carboximidothioic acid methyl ester (step d).Treatment of the iminothioether with aqueous methylamine and methylenechloride at room temperature should afford the pyrazole-1-carboxamidines(step e). Removal of the trityl group with aqueous TFA in THF at roomtemperature should yield the unprotected tetrazole (step f).

Scheme 9 shows how to convert 2′-, 3′-, or 4′-polyethoxylated analogs of2-phenylacetophenones, prepared from commercially available 2′-, 3′- or4′-methoxy-2-phenylacetophenones via O-demethylation using HBr/HOAc orBBr₃/CH₂Cl₂ and alkylation of the resultant phenols with alkyl-capped orTBDMS-capped halides prepared as described in Nuclear Medicine andBiology, 32, 799 (2005). Treatment of these polyether ketones in 37%aqueous formaldehyde containing piperidine under reflux should give thecorresponding acrylophenones (step a). Treatment of the acrylophenoneswith hydrazine hydrate in ethanol can produce the 3,4-diarylpyrazolines(step b). The diarylpyrazolines can be further treated witharylsulfonyldithioimidocarbonic acid methyl esters, prepared from thecorresponding aryl sulfonamides, CS₂ and MeI (see J. Med. Chem., 47, 627(2004); Chem. Ber. 1966, 99, 2885), in a solvent (e.g., acetonitrile) inthe presence of triethylamine at reflux to yield thepyrazole-1-carboximidothioic acid methyl ester (step c). Furtherexposure of these iminothioethers to an aqueous solution of methylamineand methylene chloride at room temperature should afford thepyrazoline-1-carboxamidines (step d). Removal of the TBDMS-capping groupusing anhydrous tetrabutylammonium fluoride in THF should produce thehydroxyl-PEG analog (step e).

One stereoisomer of a compound of the present invention may be a morepotent cannabinoid receptor antagonist than its counterpart(s). Thus,stereoisomers are included in the present invention. When required,separation of the racemic material can be achieved by HPLC using achiral column or by a resolution using a resolving agent such asdescribed in Wilen, S. H. Tables of Resolving Agents and OpticalResolutions 1972, 308 or using enantiomerically pure acids and bases. Achiral compound of the present invention may also be directlysynthesized using a chiral catalyst or a chiral ligand, e.g., Jacobsen,E. Acc. Chem. Res. 2000, 33, 421-431 or using other enantio- anddiastereo-selective reactions and reagents known to one skilled in theart of asymmetric synthesis. Examples of stereoisomers include compoundsof formula Ia and Ib shown below.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

Tables 1a-c and 2 show representative examples of the compounds of thepresent invention. Each example in each table represents an individualspecies of the present invention.

TABLE 1a

Ex. # X X″ Y″ Z Q M 1. C(NH)NH₂ Cl H H H SO₂ 2. OCH₂-tetrazole Cl H H HSO₂ 3. tetrazole Cl H H H SO₂ 4. NHSO₂CH₃ Cl H H H SO₂ 5. OCH₂CO₂Et Cl HH H SO₂ 6. OCH₂CO₂H Cl H H H SO₂ 7. OCH₂CH═CHCO₂Et Cl H H H SO₂ 8.OCH₂CH═CHCO₂H Cl H H H SO₂ 9. NHCOCH₂CO₂Et Cl H H H SO₂ 10. NHCOCH₂CO₂HCl H H H SO₂ 11. OCH₂C₆H₄-2-CO₂Et Cl H H H SO₂ 12. OCH₂C₆H₄-3-CO₂Et Cl HH H SO₂ 13. OCH₂C₆H₄-4-CO₂Et Cl H H H SO₂ 14. OCH₂C₆H₄-2-CO₂H Cl H H HSO₂ 15. OCH₂C₆H₄-3-CO₂H Cl H H H SO₂ 16. OCH₂C₆H₄-4-CO₂H Cl H H H SO₂17. OCH₂C₆H₄-2-tetrazole Cl H H H SO₂ 18. OCH₂C₆H₄-3-tetrazole Cl H H HSO₂ 19. OCH₂C₆H₄-4-tetrazole Cl H H H SO₂ 20. C(NH)NH₂ H CF₃ H H SO₂ 21.OCH₂-tetrazole H CF₃ H H SO₂ 22. tetrazole H CF₃ H H SO₂ 23. NHSO₂CH₃ HCF₃ H H SO₂ 24. OCH₂CO₂Et H CF₃ H H SO₂ 25. OCH₂CO₂H H CF₃ H H SO₂ 26.OCH₂CH═CHCO₂Et H CF₃ H H SO₂ 27. OCH₂CH═CHCO₂H H CF₃ H H SO₂ 28.NHCOCH₂CO₂Et H CF₃ H H SO₂ 29. NHCOCH₂CO₂H H CF₃ H H SO₂ 30.OCH₂C₆H₄-2-CO₂Et H CF₃ H H SO₂ 31. OCH₂C₆H₄-3-CO₂Et H CF₃ H H SO₂ 32.OCH₂C₆H₄-4-CO₂Et H CF₃ H H SO₂ 33. OCH₂C₆H₄-2-CO₂H H CF₃ H H SO₂ 34.OCH₂C₆H₄-3-CO₂H H CF₃ H H SO₂ 35. OCH₂C₆H₄-4-CO₂H H CF₃ H H SO₂ 36.OCH₂C₆H₄-2-tetrazole H CF₃ H H SO₂ 37. OCH₂C₆H₄-3-tetrazole H CF₃ H HSO₂ 38. OCH₂C₆H₄-4-tetrazole H CF₃ H H SO₂ 39. CONH₂ C(NH)NH₂ Cl H OH HSO₂ 40. OCH₂-tetrazole Cl H OH H SO₂ 41. tetrazole Cl H OH H SO₂ 42.NHSO₂CH₃ Cl H OH H SO₂ 43. OCH₂CO₂Et Cl H OH H SO₂ 44. OCH₂CO₂H Cl H OHH SO₂ 45. OCH₂CH═CHCO₂Et Cl H OH H SO₂ 46. OCH₂CH═CHCO₂H Cl H OH H SO₂47. NHCOCH₂CO₂Et Cl H OH H SO₂ 48. NHCOCH₂CO₂H Cl H OH H SO₂ 49.OCH₂C₆H₄-2-CO₂Et Cl H OH H SO₂ 50. OCH₂C₆H₄-3-CO₂Et Cl H OH H SO₂ 51.OCH₂C₆H₄-4-CO₂Et Cl H OH H SO₂ 52. OCH₂C₆H₄-2-CO₂H Cl H OH H SO₂ 53.OCH₂C₆H₄-3-CO₂H Cl H OH H SO₂ 54. OCH₂C₆H₄-4-CO₂H Cl H OH H SO₂ 55.OCH₂C₆H₄-2-tetrazole Cl H OH H SO₂ 56. OCH₂C₆H₄-3-tetrazole Cl H OH HSO₂ 57. OCH₂C₆H₄-4-tetrazole Cl H OH H SO₂ 58. C(NH)NH₂ H CF₃ OH H SO₂59. OCH₂-tetrazole H CF₃ OH H SO₂ 60. tetrazole H CF₃ OH H SO₂ 61.NHSO₂CH₃ H CF₃ OH H SO₂ 62. OCH₂CO₂Et H CF₃ OH H SO₂ 63. OCH₂CO₂H H CF₃OH H SO₂ 64. OCH₂CH═CHCO₂Et H CF₃ OH H SO₂ 65. OCH₂CH═CHCO₂H H CF₃ OH HSO₂ 66. NHCOCH₂CO₂Et H CF₃ OH H SO₂ 67. NHCOCH₂CO₂H H CF₃ OH H SO₂ 68.OCH₂C₆H₄-2-CO₂Et H CF₃ OH H SO₂ 69. OCH₂C₆H₄-3-CO₂Et H CF₃ OH H SO₂ 70.OCH₂C₆H₄-4-CO₂Et H CF₃ OH H SO₂ 71. OCH₂C₆H₄-2-CO₂H H CF₃ OH H SO₂ 72.OCH₂C₆H₄-3-CO₂H H CF₃ OH H SO₂ 73. OCH₂C₆H₄-4-CO₂H H CF₃ OH H SO₂ 74.OCH₂C₆H₄-2-tetrazole H CF₃ OH H SO₂ 75. OCH₂C₆H₄-3-tetrazole H CF₃ OH HSO₂ 76. OCH₂C₆H₄-4-tetrazole H CF₃ OH H SO₂ 77. OCH₂-tetrazole Cl H HCH₃ SO₂ 78. tetrazole Cl H H CH₃ SO₂ 79. NHSO₂CH₃ Cl H H CH₃ SO₂ 80.OCH₂CO₂Et Cl H H CH₃ SO₂ 81. OCH₂CO₂H Cl H H CH₃ SO₂ 82. OCH₂CH═CHCO₂EtCl H H CH₃ SO₂ 83. OCH₂CH═CHCO₂H Cl H H CH₃ SO₂ 84. NHCOCH₂CO₂Et Cl H HCH₃ SO₂ 85. NHCOCH₂CO₂H Cl H H CH₃ SO₂ 86. OCH₂C₆H₄-2-CO₂Et Cl H H CH₃SO₂ 87. OCH₂C₆H₄-3-CO₂Et Cl H H CH₃ SO₂ 88. OCH₂C₆H₄-4-CO₂Et Cl H H CH₃SO₂ 89. OCH₂C₆H₄-2-CO₂H Cl H H CH₃ SO₂ 90. OCH₂C₆H₄-3-CO₂H Cl H H CH₃SO₂ 91. OCH₂C₆H₄-4-CO₂H Cl H H CH₃ SO₂ 92. OCH₂C₆H₄-2-tetrazole Cl H HCH₃ SO₂ 93. OCH₂C₆H₄-3-tetrazole Cl H H CH₃ SO₂ 94. OCH₂C₆H₄-4-tetrazoleCl H H CH₃ SO₂ 95. OCH₂-tetrazole H CF₃ H CH₃ SO₂ 96. tetrazole H CF₃ HCH₃ SO₂ 97. NHSO₂CH₃ H CF₃ H CH₃ SO₂ 98. OCH₂CO₂Et H CF₃ H CH₃ SO₂ 99.OCH₂CO₂H H CF₃ H CH₃ SO₂ 100. OCH₂CH═CHCO₂Et H CF₃ H CH₃ SO₂ 101.OCH₂CH═CHCO₂H H CF₃ H CH₃ SO₂ 102. NHCOCH₂CO₂Et H CF₃ H CH₃ SO₂ 103.NHCOCH₂CO₂H H CF₃ H CH₃ SO₂ 104. OCH₂C₆H₄-2-CO₂Et H CF₃ H CH₃ SO₂ 105.OCH₂C₆H₄-3-CO₂Et H CF₃ H CH₃ SO₂ 106. OCH₂C₆H₄-4-CO₂Et H CF₃ H CH₃ SO₂107. OCH₂C₆H₄-2-CO₂H H CF₃ H CH₃ SO₂ 108. OCH₂C₆H₄-3-CO₂H H CF₃ H CH₃SO₂ 109. OCH₂C₆H₄-4-CO₂H H CF₃ H CH₃ SO₂ 110. OCH₂C₆H₄-2-tetrazole H CF₃H CH₃ SO₂ 111. OCH₂C₆H₄-3-tetrazole H CF₃ H CH₃ SO₂ 112.OCH₂C₆H₄-4-tetrazole H CF₃ H CH₃ SO₂ 113. OCH₂-tetrazole Cl H OH CH₃ SO₂114. tetrazole Cl H OH CH₃ SO₂ 115. NHSO₂CH₃ Cl H OH CH₃ SO₂ 116.OCH₂CO₂Et Cl H OH CH₃ SO₂ 117. OCH₂CO₂H Cl H OH CH₃ SO₂ 118.OCH₂CH═CHCO₂Et Cl H OH CH₃ SO₂ 119. OCH₂CH═CHCO₂H Cl H OH CH₃ SO₂ 120.NHCOCH₂CO₂Et Cl H OH CH₃ SO₂ 121. NHCOCH₂CO₂H Cl H OH CH₃ SO₂ 122.OCH₂C₆H₄-2-CO₂Et Cl H OH CH₃ SO₂ 123. OCH₂C₆H₄-3-CO₂Et Cl H OH CH₃ SO₂124. OCH₂C₆H₄-4-CO₂Et Cl H OH CH₃ SO₂ 125. OCH₂C₆H₄-2-CO₂H Cl H OH CH₃SO₂ 126. OCH₂C₆H₄-3-CO₂H Cl H OH CH₃ SO₂ 127. OCH₂C₆H₄-4-CO₂H Cl H OHCH₃ SO₂ 128. OCH₂C₆H₄-2-tetrazole Cl H OH CH₃ SO₂ 129.OCH₂C₆H₄-3-tetrazole Cl H OH CH₃ SO₂ 130. OCH₂C₆H₄-4-tetrazole Cl H OHCH₃ SO₂ 131. OCH₂-tetrazole H CF₃ OH CH₃ SO₂ 132. tetrazole H CF₃ OH CH₃SO₂ 133. NHSO₂CH₃ H CF₃ OH CH₃ SO₂ 134. OCH₂CO₂Et H CF₃ OH CH₃ SO₂ 135.OCH₂CO₂H H CF₃ OH CH₃ SO₂ 136. OCH₂CH═CHCO₂Et H CF₃ OH CH₃ SO₂ 137.OCH₂CH═CHCO₂H H CF₃ OH CH₃ SO₂ 138. NHCOCH₂CO₂Et H CF₃ OH CH₃ SO₂ 139.NHCOCH₂CO₂H H CF₃ OH CH₃ SO₂ 140. OCH₂C₆H₄-2-CO₂Et H CF₃ OH CH₃ SO₂ 141.OCH₂C₆H₄-3-CO₂Et H CF₃ OH CH₃ SO₂ 142. OCH₂C₆H₄-4-CO₂Et H CF₃ OH CH₃ SO₂143. OCH₂C₆H₄-2-CO₂H H CF₃ OH CH₃ SO₂ 144. OCH₂C₆H₄-3-CO₂H H CF₃ OH CH₃SO₂ 145. OCH₂C₆H₄-4-CO₂H H CF₃ OH CH₃ SO₂ 146. OCH₂C₆H₄-2-tetrazole HCF₃ OH CH₃ SO₂ 147. OCH₂C₆H₄-3-tetrazole H CF₃ OH CH₃ SO₂ 148.OCH₂C₆H₄-4-tetrazole H CF₃ OH CH₃ SO₂ 149. C(NH)NH₂ Cl H H H CO 150.OCH₂-tetrazole Cl H H H CO 151. tetrazole Cl H H H CO 152. NHSO₂CH₃ Cl HH H CO 153. OCH₂CO₂Et Cl H H H CO 154. OCH₂CO₂H Cl H H H CO 155.OCH₂CH═CHCO₂Et Cl H H H CO 156. OCH₂CH═CHCO₂H Cl H H H CO 157.NHCOCH₂CO₂Et Cl H H H CO 158. NHCOCH₂CO₂H Cl H H H CO 159.OCH₂C₆H₄-2-CO₂Et Cl H H H CO 160. OCH₂C₆H₄-3-CO₂Et Cl H H H CO 161.OCH₂C₆H₄-4-CO₂Et Cl H H H CO 162. OCH₂C₆H₄-2-CO₂H Cl H H H CO 163.OCH₂C₆H₄-3-CO₂H Cl H H H CO 164. OCH₂C₆H₄-4-CO₂H Cl H H H CO 165.OCH₂C₆H₄-2-tetrazole Cl H H H CO 166. OCH₂C₆H₄-3-tetrazole Cl H H H CO167. OCH₂C₆H₄-4-tetrazole Cl H H H CO 168. C(NH)NH₂ H CF₃ H H CO 169.OCH₂-tetrazole H CF₃ H H CO 170. tetrazole H CF₃ H H CO 171. NHSO₂CH₃ HCF₃ H H CO 172. OCH₂CO₂Et H CF₃ H H CO 173. OCH₂CO₂H H CF₃ H H CO 174.OCH₂CH═CHCO₂Et H CF₃ H H CO 175. OCH₂CH═CHCO₂H H CF₃ H H CO 176.NHCOCH₂CO₂Et H CF₃ H H CO 177. NHCOCH₂CO₂H H CF₃ H H CO 178.OCH₂C₆H₄-2-CO₂Et H CF₃ H H CO 179. OCH₂C₆H₄-3-CO₂Et H CF₃ H H CO 180.OCH₂C₆H₄-4-CO₂Et H CF₃ H H CO 181. OCH₂C₆H₄-2-CO₂H H CF₃ H H CO 182.OCH₂C₆H₄-3-CO₂H H CF₃ H H CO 183. OCH₂C₆H₄-4-CO₂H H CF₃ H H CO 184.OCH₂C₆H₄-2-tetrazole H CF₃ H H CO 185. OCH₂C₆H₄-3-tetrazole H CF₃ H H CO186. OCH₂C₆H₄-4-tetrazole H CF₃ H H CO 187. C(NH)NH₂ Cl H OH H CO 188.OCH₂-tetrazole Cl H OH H CO 189. tetrazole Cl H OH H CO 190. NHSO₂CH₃ ClH OH H CO 191. OCH₂CO₂Et Cl H OH H CO 192. OCH₂CO₂H Cl H OH H CO 193.OCH₂CH═CHCO₂Et Cl H OH H CO 194. OCH₂CH═CHCO₂H Cl H OH H CO 195.NHCOCH₂CO₂Et Cl H OH H CO 196. NHCOCH₂CO₂H Cl H OH H CO 197.OCH₂C₆H₄-2-CO₂Et Cl H OH H CO 198. OCH₂C₆H₄-3-CO₂Et Cl H OH H CO 199.OCH₂C₆H₄-4-CO₂Et Cl H OH H CO 200. OCH₂C₆H₄-2-CO₂H Cl H OH H CO 201.OCH₂C₆H₄-3-CO₂H Cl H OH H CO 202. OCH₂C₆H₄-4-CO₂H Cl H OH H CO 203.OCH₂C₆H₄-2-tetrazole Cl H OH H CO 204. OCH₂C₆H₄-3-tetrazole Cl H OH H CO205. OCH₂C₆H₄-4-tetrazole Cl H OH H CO 206. C(NH)NH₂ H CF₃ OH H CO 207.OCH₂-tetrazole H CF₃ OH H CO 208. tetrazole H CF₃ OH H CO 209. NHSO₂CH₃H CF₃ OH H CO 210. OCH₂CO₂Et H CF₃ OH H CO 211. OCH₂CO₂H H CF₃ OH H CO212. OCH₂CH═CHCO₂Et H CF₃ OH H CO 213. OCH₂CH═CHCO₂H H CF₃ OH H CO 214.NHCOCH₂CO₂Et H CF₃ OH H CO 215. NHCOCH₂CO₂H H CF₃ OH H CO 216.OCH₂C₆H₄-2-CO₂Et H CF₃ OH H CO 217. OCH₂C₆H₄-3-CO₂Et H CF₃ OH H CO 218.OCH₂C₆H₄-4-CO₂Et H CF₃ OH H CO 219. OCH₂C₆H₄-2-CO₂H H CF₃ OH H CO 220.OCH₂C₆H₄-3-CO₂H H CF₃ OH H CO 221. OCH₂C₆H₄-4-CO₂H H CF₃ OH H CO 222.OCH₂C₆H₄-2-tetrazole H CF₃ OH H CO 223. OCH₂C₆H₄-3-tetrazole H CF₃ OH HCO 224. OCH₂C₆H₄-4-tetrazole H CF₃ OH H CO 225. OCH₂-tetrazole Cl H HCH₃ CO 226. tetrazole Cl H H CH₃ CO 227. NHSO₂CH₃ Cl H H CH₃ CO 228.OCH₂CO₂Et Cl H H CH₃ CO 229. OCH₂CO₂H Cl H H CH₃ CO 230. OCH₂CH═CHCO₂EtCl H H CH₃ CO 231. OCH₂CH═CHCO₂H Cl H H CH₃ CO 232. NHCOCH₂CO₂Et Cl H HCH₃ CO 233. NHCOCH₂CO₂H Cl H H CH₃ CO 234. OCH₂C₆H₄-2-CO₂Et Cl H H CH₃CO 235. OCH₂C₆H₄-3-CO₂Et Cl H H CH₃ CO 236. OCH₂C₆H₄-4-CO₂Et Cl H H CH₃CO 237. OCH₂C₆H₄-2-CO₂H Cl H H CH₃ CO 238. OCH₂C₆H₄-3-CO₂H Cl H H CH₃ CO239. OCH₂C₆H₄-4-CO₂H Cl H H CH₃ CO 240. OCH₂C₆H₄-2-tetrazole Cl H H CH₃CO 241. OCH₂C₆H₄-3-tetrazole Cl H H CH₃ CO 242. OCH₂C₆H₄-4-tetrazole ClH H CH₃ CO 243. OCH₂-tetrazole H CF₃ H CH₃ CO 244. tetrazole H CF₃ H CH₃CO 245. NHSO₂CH₃ H CF₃ H CH₃ CO 246. OCH₂CO₂Et H CF₃ H CH₃ CO 247.OCH₂CO₂H H CF₃ H CH₃ CO 248. OCH₂CH═CHCO₂Et H CF₃ H CH₃ CO 249.OCH₂CH═CHCO₂H H CF₃ H CH₃ CO 250. NHCOCH₂CO₂Et H CF₃ H CH₃ CO 251.NHCOCH₂CO₂H H CF₃ H CH₃ CO 252. OCH₂C₆H₄-2-CO₂Et H CF₃ H CH₃ CO 253.OCH₂C₆H₄-3-CO₂Et H CF₃ H CH₃ CO 254. OCH₂C₆H₄-4-CO₂Et H CF₃ H CH₃ CO255. OCH₂C₆H₄-2-CO₂H H CF₃ H CH₃ CO 256. OCH₂C₆H₄-3-CO₂H H CF₃ H CH₃ CO257. OCH₂C₆H₄-4-CO₂H H CF₃ H CH₃ CO 258. OCH₂C₆H₄-2-tetrazole H CF₃ HCH₃ CO 259. OCH₂C₆H₄-3-tetrazole H CF₃ H CH₃ CO 260.OCH₂C₆H₄-4-tetrazole H CF₃ H CH₃ CO 261. OCH₂-tetrazole Cl H OH CH₃ CO262. tetrazole Cl H OH CH₃ CO 263. NHSO₂CH₃ Cl H OH CH₃ CO 264.OCH₂CO₂Et Cl H OH CH₃ CO 265. OCH₂CO₂H Cl H OH CH₃ CO 266.OCH₂CH═CHCO₂Et Cl H OH CH₃ CO 267. OCH₂CH═CHCO₂H Cl H OH CH₃ CO 268.NHCOCH₂CO₂Et Cl H OH CH₃ CO 269. NHCOCH₂CO₂H Cl H OH CH₃ CO 270.OCH₂C₆H₄-2-CO₂Et Cl H OH CH₃ CO 271. OCH₂C₆H₄-3-CO₂Et Cl H OH CH₃ CO272. OCH₂C₆H₄-4-CO₂Et Cl H OH CH₃ CO 273. OCH₂C₆H₄-2-CO₂H Cl H OH CH₃ CO274. OCH₂C₆H₄-3-CO₂H Cl H OH CH₃ CO 275. OCH₂C₆H₄-4-CO₂H Cl H OH CH₃ CO276. OCH₂C₆H₄-2-tetrazole Cl H OH CH₃ CO 277. OCH₂C₆H₄-3-tetrazole Cl HOH CH₃ CO 278. OCH₂C₆H₄-4-tetrazole Cl H OH CH₃ CO 279. OCH₂-tetrazole HCF₃ OH CH₃ CO 280. tetrazole H CF₃ OH CH₃ CO 281. NHSO₂CH₃ H CF₃ OH CH₃CO 282. OCH₂CO₂Et H CF₃ OH CH₃ CO 283. OCH₂CO₂H H CF₃ OH CH₃ CO 284.OCH₂CH═CHCO₂Et H CF₃ OH CH₃ CO 285. OCH₂CH═CHCO₂H H CF₃ OH CH₃ CO 286.NHCOCH₂CO₂Et H CF₃ OH CH₃ CO 287. NHCOCH₂CO₂H H CF₃ OH CH₃ CO 288.OCH₂C₆H₄-2-CO₂Et H CF₃ OH CH₃ CO 289. OCH₂C₆H₄-3-CO₂Et H CF₃ OH CH₃ CO290. OCH₂C₆H₄-4-CO₂Et H CF₃ OH CH₃ CO 291. OCH₂C₆H₄-2-CO₂H H CF₃ OH CH₃CO 292. OCH₂C₆H₄-3-CO₂H H CF₃ OH CH₃ CO 293. OCH₂C₆H₄-4-CO₂H H CF₃ OHCH₃ CO 294. OCH₂C₆H₄-2-tetrazole H CF₃ OH CH₃ CO 295.OCH₂C₆H₄-3-tetrazole H CF₃ OH CH₃ CO 296. OCH₂C₆H₄-4-tetrazole H CF₃ OHCH₃ CO

TABLE 1b

Ex. # X′ X″ Y″ Z Q M 1. C(NH)NH₂ Cl H H H SO₂ 2. OCH₂-tetrazole Cl H H HSO₂ 3. tetrazole Cl H H H SO₂ 4. NHSO₂CH₃ Cl H H H SO₂ 5. OCH₂CO₂Et Cl HH H SO₂ 6. OCH₂CO₂H Cl H H H SO₂ 7. OCH₂CH═CHCO₂Et Cl H H H SO₂ 8.OCH₂CH═CHCO₂H Cl H H H SO₂ 9. NHCOCH₂CO₂Et Cl H H H SO₂ 10. NHCOCH₂CO₂HCl H H H SO₂ 11. OCH₂C₆H₄-2-CO₂Et Cl H H H SO₂ 12. OCH₂C₆H₄-3-CO₂Et Cl HH H SO₂ 13. OCH₂C₆H₄-4-CO₂Et Cl H H H SO₂ 14. OCH₂C₆H₄-2-CO₂H Cl H H HSO₂ 15. OCH₂C₆H₄-3-CO₂H Cl H H H SO₂ 16. OCH₂C₆H₄-4-CO₂H Cl H H H SO₂17. OCH₂C₆H₄-2-tetrazole Cl H H H SO₂ 18. OCH₂C₆H₄-3-tetrazole Cl H H HSO₂ 19. OCH₂C₆H₄-4-tetrazole Cl H H H SO₂ 20. C(NH)NH₂ H CF₃ H H SO₂ 21.OCH₂-tetrazole H CF₃ H H SO₂ 22. tetrazole H CF₃ H H SO₂ 23. NHSO₂CH₃ HCF₃ H H SO₂ 24. OCH₂CO₂Et H CF₃ H H SO₂ 25. OCH₂CO₂H H CF₃ H H SO₂ 26.OCH₂CH═CHCO₂Et H CF₃ H H SO₂ 27. OCH₂CH═CHCO₂H H CF₃ H H SO₂ 28.NHCOCH₂CO₂Et H CF₃ H H SO₂ 29. NHCOCH₂CO₂H H CF₃ H H SO₂ 30.OCH₂C₆H₄-2-CO₂Et H CF₃ H H SO₂ 31. OCH₂C₆H₄-3-CO₂Et H CF₃ H H SO₂ 32.OCH₂C₆H₄-4-CO₂Et H CF₃ H H SO₂ 33. OCH₂C₆H₄-2-CO₂H H CF₃ H H SO₂ 34.OCH₂C₆H₄-3-CO₂H H CF₃ H H SO₂ 35. OCH₂C₆H₄-4-CO₂H H CF₃ H H SO₂ 36.OCH₂C₆H₄-2-tetrazole H CF₃ H H SO₂ 37. OCH₂C₆H₄-3-tetrazole H CF₃ H HSO₂ 38. OCH₂C₆H₄-4-tetrazole H CF₃ H H SO₂ 39. C(NH)NH₂ Cl H OH H SO₂40. OCH₂-tetrazole Cl H OH H SO₂ 41. tetrazole Cl H OH H SO₂ 42.NHSO₂CH₃ Cl H OH H SO₂ 43. OCH₂CO₂Et Cl H OH H SO₂ 44. OCH₂CO₂H Cl H OHH SO₂ 45. OCH₂CH═CHCO₂Et Cl H OH H SO₂ 46. OCH₂CH═CHCO₂H Cl H OH H SO₂47. NHCOCH₂CO₂Et Cl H OH H SO₂ 48. NHCOCH₂CO₂H Cl H OH H SO₂ 49.OCH₂C₆H₄-2-CO₂Et Cl H OH H SO₂ 50. OCH₂C₆H₄-3-CO₂Et Cl H OH H SO₂ 51.OCH₂C₆H₄-4-CO₂Et Cl H OH H SO₂ 52. OCH₂C₆H₄-2-CO₂H Cl H OH H SO₂ 53.OCH₂C₆H₄-3-CO₂H Cl H OH H SO₂ 54. OCH₂C₆H₄-4-CO₂H Cl H OH H SO₂ 55.OCH₂C₆H₄-2-tetrazole Cl H OH H SO₂ 56. OCH₂C₆H₄-3-tetrazole Cl H OH HSO₂ 57. OCH₂C₆H₄-4-tetrazole Cl H OH H SO₂ 58. C(NH)NH₂ H CF₃ OH H SO₂59. OCH₂-tetrazole H CF₃ OH H SO₂ 60. tetrazole H CF₃ OH H SO₂ 61.NHSO₂CH₃ H CF₃ OH H SO₂ 62. OCH₂CO₂Et H CF₃ OH H SO₂ 63. OCH₂CO₂H H CF₃OH H SO₂ 64. OCH₂CH═CHCO₂Et H CF₃ OH H SO₂ 65. OCH₂CH═CHCO₂H H CF₃ OH HSO₂ 66. NHCOCH₂CO₂Et H CF₃ OH H SO₂ 67. NHCOCH₂CO₂H H CF₃ OH H SO₂ 68.OCH₂C₆H₄-2-CO₂Et H CF₃ OH H SO₂ 69. OCH₂C₆H₄-3-CO₂Et H CF₃ OH H SO₂ 70.OCH₂C₆H₄-4-CO₂Et H CF₃ OH H SO₂ 71. OCH₂C₆H₄-2-CO₂H H CF₃ OH H SO₂ 72.OCH₂C₆H₄-3-CO₂H H CF₃ OH H SO₂ 73. OCH₂C₆H₄-4-CO₂H H CF₃ OH H SO₂ 74.OCH₂C₆H₄-2-tetrazole H CF₃ OH H SO₂ 75. OCH₂C₆H₄-3-tetrazole H CF₃ OH HSO₂ 76. OCH₂C₆H₄-4-tetrazole H CF₃ OH H SO₂ 77. OCH₂-tetrazole Cl H HCH₃ SO₂ 78. tetrazole Cl H H CH₃ SO₂ 79. NHSO₂CH₃ Cl H H CH₃ SO₂ 80.OCH₂CO₂Et Cl H H CH₃ SO₂ 81. OCH₂CO₂H Cl H H CH₃ SO₂ 82. OCH₂CH═CHCO₂EtCl H H CH₃ SO₂ 83. OCH₂CH═CHCO₂H Cl H H CH₃ SO₂ 84. NHCOCH₂CO₂Et Cl H HCH₃ SO₂ 85. NHCOCH₂CO₂H Cl H H CH₃ SO₂ 86. OCH₂C₆H₄-2-CO₂Et Cl H H CH₃SO₂ 87. OCH₂C₆H₄-3-CO₂Et Cl H H CH₃ SO₂ 88. OCH₂C₆H₄-4-CO₂Et Cl H H CH₃SO₂ 89. OCH₂C₆H₄-2-CO₂H Cl H H CH₃ SO₂ 90. OCH₂C₆H₄-3-CO₂H Cl H H CH₃SO₂ 91. OCH₂C₆H₄-4-CO₂H Cl H H CH₃ SO₂ 92. OCH₂C₆H₄-2-tetrazole Cl H HCH₃ SO₂ 93. OCH₂C₆H₄-3-tetrazole Cl H H CH₃ SO₂ 94. OCH₂C₆H₄-4-tetrazoleCl H H CH₃ SO₂ 95. OCH₂-tetrazole H CF₃ H CH₃ SO₂ 96. tetrazole H CF₃ HCH₃ SO₂ 97. NHSO₂CH₃ H CF₃ H CH₃ SO₂ 98. OCH₂CO₂Et H CF₃ H CH₃ SO₂ 99.OCH₂CO₂H H CF₃ H CH₃ SO₂ 100. OCH₂CH═CHCO₂Et H CF₃ H CH₃ SO₂ 101.OCH₂CH═CHCO₂H H CF₃ H CH₃ SO₂ 102. NHCOCH₂CO₂Et H CF₃ H CH₃ SO₂ 103.NHCOCH₂CO₂H H CF₃ H CH₃ SO₂ 104. OCH₂C₆H₄-2-CO₂Et H CF₃ H CH₃ SO₂ 105.OCH₂C₆H₄-3-CO₂Et H CF₃ H CH₃ SO₂ 106. OCH₂C₆H₄-4-CO₂Et H CF₃ H CH₃ SO₂107. OCH₂C₆H₄-2-CO₂H H CF₃ H CH₃ SO₂ 108. OCH₂C₆H₄-3-CO₂H H CF₃ H CH₃SO₂ 109. OCH₂C₆H₄-4-CO₂H H CF₃ H CH₃ SO₂ 110. OCH₂C₆H₄-2-tetrazole H CF₃H CH₃ SO₂ 111. OCH₂C₆H₄-3-tetrazole H CF₃ H CH₃ SO₂ 112.OCH₂C₆H₄-4-tetrazole H CF₃ H CH₃ SO₂ 113. OCH₂-tetrazole Cl H OH CH₃ SO₂114. tetrazole Cl H OH CH₃ SO₂ 115. NHSO₂CH₃ Cl H OH CH₃ SO₂ 116.OCH₂CO₂Et Cl H OH CH₃ SO₂ 117. OCH₂CO₂H Cl H OH CH₃ SO₂ 118.OCH₂CH═CHCO₂Et Cl H OH CH₃ SO₂ 119. OCH₂CH═CHCO₂H Cl H OH CH₃ SO₂ 120.NHCOCH₂CO₂Et Cl H OH CH₃ SO₂ 121. NHCOCH₂CO₂H Cl H OH CH₃ SO₂ 122.OCH₂C₆H₄-2-CO₂Et Cl H OH CH₃ SO₂ 123. OCH₂C₆H₄-3-CO₂Et Cl H OH CH₃ SO₂124. OCH₂C₆H₄-4-CO₂Et Cl H OH CH₃ SO₂ 125. OCH₂C₆H₄-2-CO₂H Cl H OH CH₃SO₂ 126. OCH₂C₆H₄-3-CO₂H Cl H OH CH₃ SO₂ 127. OCH₂C₆H₄-4-CO₂H Cl H OHCH₃ SO₂ 128. OCH₂C₆H₄-2-tetrazole Cl H OH CH₃ SO₂ 129.OCH₂C₆H₄-3-tetrazole Cl H OH CH₃ SO₂ 130. OCH₂C₆H₄-4-tetrazole Cl H OHCH₃ SO₂ 131. OCH₂-tetrazole H CF₃ OH CH₃ SO₂ 132. tetrazole H CF₃ OH CH₃SO₂ 133. NHSO₂CH₃ H CF₃ OH CH₃ SO₂ 134. OCH₂CO₂Et H CF₃ OH CH₃ SO₂ 135.OCH₂CO₂H H CF₃ OH CH₃ SO₂ 136. OCH₂CH═CHCO₂Et H CF₃ OH CH₃ SO₂ 137.OCH₂CH═CHCO₂H H CF₃ OH CH₃ SO₂ 138. NHCOCH₂CO₂Et H CF₃ OH CH₃ SO₂ 139.NHCOCH₂CO₂H H CF₃ OH CH₃ SO₂ 140. OCH₂C₆H₄-2-CO₂Et H CF₃ OH CH₃ SO₂ 141.OCH₂C₆H₄-3-CO₂Et H CF₃ OH CH₃ SO₂ 142. OCH₂C₆H₄-4-CO₂Et H CF₃ OH CH₃ SO₂143. OCH₂C₆H₄-2-CO₂H H CF₃ OH CH₃ SO₂ 144. OCH₂C₆H₄-3-CO₂H H CF₃ OH CH₃SO₂ 145. OCH₂C₆H₄-4-CO₂H H CF₃ OH CH₃ SO₂ 146. OCH₂C₆H₄-2-tetrazole HCF₃ OH CH₃ SO₂ 147. OCH₂C₆H₄-3-tetrazole H CF₃ OH CH₃ SO₂ 148.OCH₂C₆H₄-4-tetrazole H CF₃ OH CH₃ SO₂ 149. C(NH)NH₂ Cl H H H CO 150.OCH₂-tetrazole Cl H H H CO 151. tetrazole Cl H H H CO 152. NHSO₂CH₃ Cl HH H CO 153. OCH₂CO₂Et Cl H H H CO 154. OCH₂CO₂H Cl H H H CO 155.OCH₂CH═CHCO₂Et Cl H H H CO 156. OCH₂CH═CHCO₂H Cl H H H CO 157.NHCOCH₂CO₂Et Cl H H H CO 158. NHCOCH₂CO₂H Cl H H H CO 159.OCH₂C₆H₄-2-CO₂Et Cl H H H CO 160. OCH₂C₆H₄-3-CO₂Et Cl H H H CO 161.OCH₂C₆H₄-4-CO₂Et Cl H H H CO 162. OCH₂C₆H₄-2-CO₂H Cl H H H CO 163.OCH₂C₆H₄-3-CO₂H Cl H H H CO 164. OCH₂C₆H₄-4-CO₂H Cl H H H CO 165.OCH₂C₆H₄-2-tetrazole Cl H H H CO 166. OCH₂C₆H₄-3-tetrazole Cl H H H CO167. OCH₂C₆H₄-4-tetrazole Cl H H H CO 168. C(NH)NH₂ H CF₃ H H CO 169.OCH₂-tetrazole H CF₃ H H CO 170. tetrazole H CF₃ H H CO 171. NHSO₂CH₃ HCF₃ H H CO 172. OCH₂CO₂Et H CF₃ H H CO 173. OCH₂CO₂H H CF₃ H H CO 174.OCH₂CH═CHCO₂Et H CF₃ H H CO 175. OCH₂CH═CHCO₂H H CF₃ H H CO 176.NHCOCH₂CO₂Et H CF₃ H H CO 177. NHCOCH₂CO₂H H CF₃ H H CO 178.OCH₂C₆H₄-2-CO₂Et H CF₃ H H CO 179. OCH₂C₆H₄-3-CO₂Et H CF₃ H H CO 180.OCH₂C₆H₄-4-CO₂Et H CF₃ H H CO 181. OCH₂C₆H₄-2-CO₂H H CF₃ H H CO 182.OCH₂C₆H₄-3-CO₂H H CF₃ H H CO 183. OCH₂C₆H₄-4-CO₂H H CF₃ H H CO 184.OCH₂C₆H₄-2-tetrazole H CF₃ H H CO 185. OCH₂C₆H₄-3-tetrazole H CF₃ H H CO186. OCH₂C₆H₄-4-tetrazole H CF₃ H H CO 187. C(NH)NH₂ Cl H OH H CO 188.OCH₂-tetrazole Cl H OH H CO 189. tetrazole Cl H OH H CO 190. NHSO₂CH₃ ClH OH H CO 191. OCH₂CO₂Et Cl H OH H CO 192. OCH₂CO₂H Cl H OH H CO 193.OCH₂CH═CHCO₂Et Cl H OH H CO 194. OCH₂CH═CHCO₂H Cl H OH H CO 195.NHCOCH₂CO₂Et Cl H OH H CO 196. NHCOCH₂CO₂H Cl H OH H CO 197.OCH₂C₆H₄-2-CO₂Et Cl H OH H CO 198. OCH₂C₆H₄-3-CO₂Et Cl H OH H CO 199.OCH₂C₆H₄-4-CO₂Et Cl H OH H CO 200. OCH₂C₆H₄-2-CO₂H Cl H OH H CO 201.OCH₂C₆H₄-3-CO₂H Cl H OH H CO 202. OCH₂C₆H₄-4-CO₂H Cl H OH H CO 203.OCH₂C₆H₄-2-tetrazole Cl H OH H CO 204. OCH₂C₆H₄-3-tetrazole Cl H OH H CO205. OCH₂C₆H₄-4-tetrazole Cl H OH H CO 206. C(NH)NH₂ H CF₃ OH H CO 207.OCH₂-tetrazole H CF₃ OH H CO 208. tetrazole H CF₃ OH H CO 209. NHSO₂CH₃H CF₃ OH H CO 210. OCH₂CO₂Et H CF₃ OH H CO 211. OCH₂CO₂H H CF₃ OH H CO212. OCH₂CH═CHCO₂Et H CF₃ OH H CO 213. OCH₂CH═CHCO₂H H CF₃ OH H CO 214.NHCOCH₂CO₂Et H CF₃ OH H CO 215. NHCOCH₂CO₂H H CF₃ OH H CO 216.OCH₂C₆H₄-2-CO₂Et H CF₃ OH H CO 217. OCH₂C₆H₄-3-CO₂Et H CF₃ OH H CO 218.OCH₂C₆H₄-4-CO₂Et H CF₃ OH H CO 219. OCH₂C₆H₄-2-CO₂H H CF₃ OH H CO 220.OCH₂C₆H₄-3-CO₂H H CF₃ OH H CO 221. OCH₂C₆H₄-4-CO₂H H CF₃ OH H CO 222.OCH₂C₆H₄-2-tetrazole H CF₃ OH H CO 223. OCH₂C₆H₄-3-tetrazole H CF₃ OH HCO 224. OCH₂C₆H₄-4-tetrazole H CF₃ OH H CO 225. OCH₂-tetrazole Cl H HCH₃ CO 226. tetrazole Cl H H CH₃ CO 227. NHSO₂CH₃ Cl H H CH₃ CO 228.OCH₂CO₂Et Cl H H CH₃ CO 229. OCH₂CO₂H Cl H H CH₃ CO 230. OCH₂CH═CHCO₂EtCl H H CH₃ CO 231. OCH₂CH═CHCO₂H Cl H H CH₃ CO 232. NHCOCH₂CO₂Et Cl H HCH₃ CO 233. NHCOCH₂CO₂H Cl H H CH₃ CO 234. OCH₂C₆H₄-2-CO₂Et Cl H H CH₃CO 235. OCH₂C₆H₄-3-CO₂Et Cl H H CH₃ CO 236. OCH₂C₆H₄-4-CO₂Et Cl H H CH₃CO 237. OCH₂C₆H₄-2-CO₂H Cl H H CH₃ CO 238. OCH₂C₆H₄-3-CO₂H Cl H H CH₃ CO239. OCH₂C₆H₄-4-CO₂H Cl H H CH₃ CO 240. OCH₂C₆H₄-2-tetrazole Cl H H CH₃CO 241. OCH₂C₆H₄-3-tetrazole Cl H H CH₃ CO 242. OCH₂C₆H₄-4-tetrazole ClH H CH₃ CO 243. OCH₂-tetrazole H CF₃ H CH₃ CO 244. tetrazole H CF₃ H CH₃CO 245. NHSO₂CH₃ H CF₃ H CH₃ CO 246. OCH₂CO₂Et H CF₃ H CH₃ CO 247.OCH₂CO₂H H CF₃ H CH₃ CO 248. OCH₂CH═CHCO₂Et H CF₃ H CH₃ CO 249.OCH₂CH═CHCO₂H H CF₃ H CH₃ CO 250. NHCOCH₂CO₂Et H CF₃ H CH₃ CO 251.NHCOCH₂CO₂H H CF₃ H CH₃ CO 252. OCH₂C₆H₄-2-CO₂Et H CF₃ H CH₃ CO 253.OCH₂C₆H₄-3-CO₂Et H CF₃ H CH₃ CO 254. OCH₂C₆H₄-4-CO₂Et H CF₃ H CH₃ CO255. OCH₂C₆H₄-2-CO₂H H CF₃ H CH₃ CO 256. OCH₂C₆H₄-3-CO₂H H CF₃ H CH₃ CO257. OCH₂C₆H₄-4-CO₂H H CF₃ H CH₃ CO 258. OCH₂C₆H₄-2-tetrazole H CF₃ HCH₃ CO 259. OCH₂C₆H₄-3-tetrazole H CF₃ H CH₃ CO 260.OCH₂C₆H₄-4-tetrazole H CF₃ H CH₃ CO 261. OCH₂-tetrazole Cl H OH CH₃ CO262. tetrazole Cl H OH CH₃ CO 263. NHSO₂CH₃ Cl H OH CH₃ CO 264.OCH₂CO₂Et Cl H OH CH₃ CO 265. OCH₂CO₂H Cl H OH CH₃ CO 266.OCH₂CH═CHCO₂Et Cl H OH CH₃ CO 267. OCH₂CH═CHCO₂H Cl H OH CH₃ CO 268.NHCOCH₂CO₂Et Cl H OH CH₃ CO 269. NHCOCH₂CO₂H Cl H OH CH₃ CO 270.OCH₂C₆H₄-2-CO₂Et Cl H OH CH₃ CO 271. OCH₂C₆H₄-3-CO₂Et Cl H OH CH₃ CO272. OCH₂C₆H₄-4-CO₂Et Cl H OH CH₃ CO 273. OCH₂C₆H₄-2-CO₂H Cl H OH CH₃ CO274. OCH₂C₆H₄-3-CO₂H Cl H OH CH₃ CO 275. OCH₂C₆H₄-4-CO₂H Cl H OH CH₃ CO276. OCH₂C₆H₄-2-tetrazole Cl H OH CH₃ CO 277. OCH₂C₆H₄-3-tetrazole Cl HOH CH₃ CO 278. OCH₂C₆H₄-4-tetrazole Cl H OH CH₃ CO 279. OCH₂-tetrazole HCF₃ OH CH₃ CO 280. tetrazole H CF₃ OH CH₃ CO 281. NHSO₂CH₃ H CF₃ OH CH₃CO 282. OCH₂CO₂Et H CF₃ OH CH₃ CO 283. OCH₂CO₂H H CF₃ OH CH₃ CO 284.OCH₂CH═CHCO₂Et H CF₃ OH CH₃ CO 285. OCH₂CH═CHCO₂H H CF₃ OH CH₃ CO 286.NHCOCH₂CO₂Et H CF₃ OH CH₃ CO 287. NHCOCH₂CO₂H H CF₃ OH CH₃ CO 288.OCH₂C₆H₄-2-CO₂Et H CF₃ OH CH₃ CO 289. OCH₂C₆H₄-3-CO₂Et H CF₃ OH CH₃ CO290. OCH₂C₆H₄-4-CO₂Et H CF₃ OH CH₃ CO 291. OCH₂C₆H₄-2-CO₂H H CF₃ OH CH₃CO 292. OCH₂C₆H₄-3-CO₂H H CF₃ OH CH₃ CO 293. OCH₂C₆H₄-4-CO₂H H CF₃ OHCH₃ CO 294. OCH₂C₆H₄-2-tetrazole H CF₃ OH CH₃ CO 295.OCH₂C₆H₄-3-tetrazole H CF₃ OH CH₃ CO 296. OCH₂C₆H₄-4-tetrazole H CF₃ OHCH₃ CO

TABLE 1c

Ex. # X″ Z Q M  1. C(NH)NH₂ H H SO₂  2. OCH₂-tetrazole H H SO₂  3.tetrazole H H SO₂  4. NHSO₂CH₃ H H SO₂  5. OCH₂CO₂Et H H SO₂  6.OCH₂CO₂H H H SO₂  7. OCH₂CH═CHCO₂Et H H SO₂  8. OCH₂CH═CHCO₂H H H SO₂ 9. NHCOCH₂CO₂Et H H SO₂  10. NHCOCH₂CO₂H H H SO₂  11. OCH₂C₆H₄-2-CO₂EtH H SO₂  12. OCH₂C₆H₄-3-CO₂Et H H SO₂  13. OCH₂C₆H₄-4-CO₂Et H H SO₂  14.OCH₂C₆H₄-2-CO₂H H H SO₂  15. OCH₂C₆H₄-3-CO₂H H H SO₂  16.OCH₂C₆H₄-4-CO₂H H H SO₂  17. OCH₂C₆H₄-2-tetrazole H H SO₂  18.OCH₂C₆H₄-3-tetrazole H H SO₂  19. OCH₂C₆H₄-4-tetrazole H H SO₂  20.C(NH)NH₂ OH H SO₂  21. OCH₂-tetrazole OH H SO₂  22. tetrazole OH H SO₂ 23. NHSO₂CH₃ OH H SO₂  24. OCH₂CO₂Et OH H SO₂  25. OCH₂CO₂H OH H SO₂ 26. OCH₂CH═CHCO₂Et OH H SO₂  27. OCH₂CH═CHCO₂H OH H SO₂  28.NHCOCH₂CO₂Et OH H SO₂  29. NHCOCH₂CO₂H OH H SO₂  30. OCH₂C₆H₄-2-CO₂Et OHH SO₂  31. OCH₂C₆H₄-3-CO₂Et OH H SO₂  32. OCH₂C₆H₄-4-CO₂Et OH H SO₂  33.OCH₂C₆H₄-2-CO₂H OH H SO₂  34. OCH₂C₆H₄-3-CO₂H OH H SO₂  35.OCH₂C₆H₄-4-CO₂H OH H SO₂  36. OCH₂C₆H₄-2-tetrazole OH H SO₂  37.OCH₂C₆H₄-3-tetrazole OH H SO₂  38. OCH₂C₆H₄-4-tetrazole OH H SO₂  39.OCH₂-tetrazole H CH₃ SO₂  40. tetrazole H CH₃ SO₂  41. NHSO₂CH₃ H CH₃SO₂  42. OCH₂CO₂Et H CH₃ SO₂  43. OCH₂CO₂H H CH₃ SO₂  44. OCH₂CH═CHCO₂EtH CH₃ SO₂  45. OCH₂CH═CHCO₂H H CH₃ SO₂  46. NHCOCH₂CO₂Et H CH₃ SO₂  47.NHCOCH₂CO₂H H CH₃ SO₂  48. OCH₂C₆H₄-2-CO₂Et H CH₃ SO₂  49.OCH₂C₆H₄-3-CO₂Et H CH₃ SO₂  50. OCH₂C₆H₄-4-CO₂Et H CH₃ SO₂  51.OCH₂C₆H₄-2-CO₂H H CH₃ SO₂  52. OCH₂C₆H₄-3-CO₂H H CH₃ SO₂  53.OCH₂C₆H₄-4-CO₂H H CH₃ SO₂  54. OCH₂C₆H₄-2-tetrazole H CH₃ SO₂  55.OCH₂C₆H₄-3-tetrazole H CH₃ SO₂  56. OCH₂C₆H₄-4-tetrazole H CH₃ SO₂  57.OCH₂-tetrazole OH CH₃ SO₂  58. tetrazole OH CH₃ SO₂  59. NHSO₂CH₃ OH CH₃SO₂  60. OCH₂CO₂Et OH CH₃ SO₂  61. OCH₂CO₂H OH CH₃ SO₂  62.OCH₂CH═CHCO₂Et OH CH₃ SO₂  63. OCH₂CH═CHCO₂H OH CH₃ SO₂  64.NHCOCH₂CO₂Et OH CH₃ SO₂  65. NHCOCH₂CO₂H OH CH₃ SO₂  66.OCH₂C₆H₄-2-CO₂Et OH CH₃ SO₂  67. OCH₂C₆H₄-3-CO₂Et OH CH₃ SO₂  68.OCH₂C₆H₄-4-CO₂Et OH CH₃ SO₂  69. OCH₂C₆H₄-2-CO₂H OH CH₃ SO₂  70.OCH₂C₆H₄-3-CO₂H OH CH₃ SO₂  71. OCH₂C₆H₄-4-CO₂H OH CH₃ SO₂  72.OCH₂C₆H₄-2-tetrazole OH CH₃ SO₂  73. OCH₂C₆H₄-3-tetrazole OH CH₃ SO₂ 74. OCH₂C₆H₄-4-tetrazole OH CH₃ SO₂  75. C(NH)NH₂ H H CO  76.OCH₂-tetrazole H H CO  77. tetrazole H H CO  78. NHSO₂CH₃ H H CO  79.OCH₂CO₂Et H H CO  80. OCH₂CO₂H H H CO  81. OCH₂CH═CHCO₂Et H H CO  82.OCH₂CH═CHCO₂H H H CO  83. NHCOCH₂CO₂Et H H CO  84. NHCOCH₂CO₂H H H CO 85. OCH₂C₆H₄-2-CO₂Et H H CO  86. OCH₂C₆H₄-3-CO₂Et H H CO  87.OCH₂C₆H₄-4-CO₂Et H H CO  88. OCH₂C₆H₄-2-CO₂H H H CO  89. OCH₂C₆H₄-3-CO₂HH H CO  90. OCH₂C₆H₄-4-CO₂H H H CO  91. OCH₂C₆H₄-2-tetrazole H H CO  92.OCH₂C₆H₄-3-tetrazole H H CO  93. OCH₂C₆H₄-4-tetrazole H H CO  94.C(NH)NH₂ OH H CO  95. OCH₂-tetrazole OH H CO  96. tetrazole OH H CO  97.NHSO₂CH₃ OH H CO  98. OCH₂CO₂Et OH H CO  99. OCH₂CO₂H OH H CO 100.OCH₂CH═CHCO₂Et OH H CO 101. OCH₂CH═CHCO₂H OH H CO 102. NHCOCH₂CO₂Et OH HCO 103. NHCOCH₂CO₂H OH H CO 104. OCH₂C₆H₄-2-CO₂Et OH H CO 105.OCH₂C₆H₄-3-CO₂Et OH H CO 106. OCH₂C₆H₄-4-CO₂Et OH H CO 107.OCH₂C₆H₄-2-CO₂H OH H CO 108. OCH₂C₆H₄-3-CO₂H OH H CO 109.OCH₂C₆H₄-4-CO₂H OH H CO 110. OCH₂C₆H₄-2-tetrazole OH H CO 111.OCH₂C₆H₄-3-tetrazole OH H CO 112. OCH₂C₆H₄-4-tetrazole OH H CO 113.OCH₂-tetrazole H CH₃ CO 114. tetrazole H CH₃ CO 115. NHSO₂CH₃ H CH₃ CO116. OCH₂CO₂Et H CH₃ CO 117. OCH₂CO₂H H CH₃ CO 118. OCH₂CH═CHCO₂Et H CH₃CO 119. OCH₂CH═CHCO₂H H CH₃ CO 120. NHCOCH₂CO₂Et H CH₃ CO 121.NHCOCH₂CO₂H H CH₃ CO 122. OCH₂C₆H₄-2-CO₂Et H CH₃ CO 123.OCH₂C₆H₄-3-CO₂Et H CH₃ CO 124. OCH₂C₆H₄-4-CO₂Et H CH₃ CO 125.OCH₂C₆H₄-2-CO₂H H CH₃ CO 126. OCH₂C₆H₄-3-CO₂H H CH₃ CO 127.OCH₂C₆H₄-4-CO₂H H CH₃ CO 128. OCH₂C₆H₄-2-tetrazole H CH₃ CO 129.OCH₂C₆H₄-3-tetrazole H CH₃ CO 130. OCH₂C₆H₄-4-tetrazole H CH₃ CO 131.OCH₂-tetrazole OH CH₃ CO 132. tetrazole OH CH₃ CO 133. NHSO₂CH₃ OH CH₃CO 134. OCH₂CO₂Et OH CH₃ CO 135. OCH₂CO₂H OH CH₃ CO 136. OCH₂CH═CHCO₂EtOH CH₃ CO 137. OCH₂CH═CHCO₂H OH CH₃ CO 138. NHCOCH₂CO₂Et OH CH₃ CO 139.NHCOCH₂CO₂H OH CH₃ CO 140. OCH₂C₆H₄-2-CO₂Et OH CH₃ CO 141.OCH₂C₆H₄-3-CO₂Et OH CH₃ CO 142. OCH₂C₆H₄-4-CO₂Et OH CH₃ CO 143.OCH₂C₆H₄-2-CO₂H OH CH₃ CO 144. OCH₂C₆H₄-3-CO₂H OH CH₃ CO 145.OCH₂C₆H₄-4-CO₂H OH CH₃ CO 146. OCH₂C₆H₄-2-tetrazole OH CH₃ CO 147.OCH₂C₆H₄-3-tetrazole OH CH₃ CO 148. OCH₂C₆H₄-4-tetrazole OH CH₃ CO

TABLE 1d

Ex. # Y″ Z Q M  1. C(NH)NH₂ H H SO₂  2. OCH₂-tetrazole H H SO₂  3.tetrazole H H SO₂  4. NHSO₂CH₃ H H SO₂  5. OCH₂CO₂Et H H SO₂  6.OCH₂CO₂H H H SO₂  7. OCH₂CH═CHCO₂Et H H SO₂  8. OCH₂CH═CHCO₂H H H SO₂ 9. NHCOCH₂CO₂Et H H SO₂  10. NHCOCH₂CO₂H H H SO₂  11. OCH₂C₆H₄-2-CO₂EtH H SO₂  12. OCH₂C₆H₄-3-CO₂Et H H SO₂  13. OCH₂C₆H₄-4-CO₂Et H H SO₂  14.OCH₂C₆H₄-2-CO₂H H H SO₂  15. OCH₂C₆H₄-3-CO₂H H H SO₂  16.OCH₂C₆H₄-4-CO₂H H H SO₂  17. OCH₂C₆H₄-2-tetrazole H H SO₂  18.OCH₂C₆H₄-3-tetrazole H H SO₂  19. OCH₂C₆H₄-4-tetrazole H H SO₂  20.C(NH)NH₂ OH H SO₂  21. OCH₂-tetrazole OH H SO₂  22. tetrazole OH H SO₂ 23. NHSO₂CH₃ OH H SO₂  24. OCH₂CO₂Et OH H SO₂  25. OCH₂CO₂H OH H SO₂ 26. OCH₂CH═CHCO₂Et OH H SO₂  27. OCH₂CH═CHCO₂H OH H SO₂  28.NHCOCH₂CO₂Et OH H SO₂  29. NHCOCH₂CO₂H OH H SO₂  30. OCH₂C₆H₄-2-CO₂Et OHH SO₂  31. OCH₂C₆H₄-3-CO₂Et OH H SO₂  32. OCH₂C₆H₄-4-CO₂Et OH H SO₂  33.OCH₂C₆H₄-2-CO₂H OH H SO₂  34. OCH₂C₆H₄-3-CO₂H OH H SO₂  35.OCH₂C₆H₄-4-CO₂H OH H SO₂  36. OCH₂C₆H₄-2-tetrazole OH H SO₂  37.OCH₂C₆H₄-3-tetrazole OH H SO₂  38. OCH₂C₆H₄-4-tetrazole OH H SO₂  39.OCH₂-tetrazole H CH₃ SO₂  40. tetrazole H CH₃ SO₂  41. NHSO₂CH₃ H CH₃SO₂  42. OCH₂CO₂Et H CH₃ SO₂  43. OCH₂CO₂H H CH₃ SO₂  44. OCH₂CH═CHCO₂EtH CH₃ SO₂  45. OCH₂CH═CHCO₂H H CH₃ SO₂  46. NHCOCH₂CO₂Et H CH₃ SO₂  47.NHCOCH₂CO₂H H CH₃ SO₂  48. OCH₂C₆H₄-2-CO₂Et H CH₃ SO₂  49.OCH₂C₆H₄-3-CO₂Et H CH₃ SO₂  50. OCH₂C₆H₄-4-CO₂Et H CH₃ SO₂  51.OCH₂C₆H₄-2-CO₂H H CH₃ SO₂  52. OCH₂C₆H₄-3-CO₂H H CH₃ SO₂  53.OCH₂C₆H₄-4-CO₂H H CH₃ SO₂  54. OCH₂C₆H₄-2-tetrazole H CH₃ SO₂  55.OCH₂C₆H₄-3-tetrazole H CH₃ SO₂  56. OCH₂C₆H₄-4-tetrazole H CH₃ SO₂  57.OCH₂-tetrazole OH CH₃ SO₂  58. tetrazole OH CH₃ SO₂  59. NHSO₂CH₃ OH CH₃SO₂  60. OCH₂CO₂Et OH CH₃ SO₂  61. OCH₂CO₂H OH CH₃ SO₂  62.OCH₂CH═CHCO₂Et OH CH₃ SO₂  63. OCH₂CH═CHCO₂H OH CH₃ SO₂  64.NHCOCH₂CO₂Et OH CH₃ SO₂  65. NHCOCH₂CO₂H OH CH₃ SO₂  66.OCH₂C₆H₄-2-CO₂Et OH CH₃ SO₂  67. OCH₂C₆H₄-3-CO₂Et OH CH₃ SO₂  68.OCH₂C₆H₄-4-CO₂Et OH CH₃ SO₂  69. OCH₂C₆H₄-2-CO₂H OH CH₃ SO₂  70.OCH₂C₆H₄-3-CO₂H OH CH₃ SO₂  71. OCH₂C₆H₄-4-CO₂H OH CH₃ SO₂  72.OCH₂C₆H₄-2-tetrazole OH CH₃ SO₂  73. OCH₂C₆H₄-3-tetrazole OH CH₃ SO₂ 74. OCH₂C₆H₄-4-tetrazole OH CH₃ SO₂  75. C(NH)NH₂ H H CO  76.OCH₂-tetrazole H H CO  77. tetrazole H H CO  78. NHSO₂CH₃ H H CO  79.OCH₂CO₂Et H H CO  80. OCH₂CO₂H H H CO  81. OCH₂CH═CHCO₂Et H H CO  82.OCH₂CH═CHCO₂H H H CO  83. NHCOCH₂CO₂Et H H CO  84. NHCOCH₂CO₂H H H CO 85. OCH₂C₆H₄-2-CO₂Et H H CO  86. OCH₂C₆H₄-3-CO₂Et H H CO  87.OCH₂C₆H₄-4-CO₂Et H H CO  88. OCH₂C₆H₄-2-CO₂H H H CO  89. OCH₂C₆H₄-3-CO₂HH H CO  90. OCH₂C₆H₄-4-CO₂H H H CO  91. OCH₂C₆H₄-2-tetrazole H H CO  92.OCH₂C₆H₄-3-tetrazole H H CO  93. OCH₂C₆H₄-4-tetrazole H H CO  94.C(NH)NH₂ OH H CO  95. OCH₂-tetrazole OH H CO  96. tetrazole OH H CO  97.NHSO₂CH₃ OH H CO  98. OCH₂CO₂Et OH H CO  99. OCH₂CO₂H OH H CO 100.OCH₂CH═CHCO₂Et OH H CO 101. OCH₂CH═CHCO₂H OH H CO 102. NHCOCH₂CO₂Et OH HCO 103. NHCOCH₂CO₂H OH H CO 104. OCH₂C₆H₄-2-CO₂Et OH H CO 105.OCH₂C₆H₄-3-CO₂Et OH H CO 106. OCH₂C₆H₄-4-CO₂Et OH H CO 107.OCH₂C₆H₄-2-CO₂H OH H CO 108. OCH₂C₆H₄-3-CO₂H OH H CO 109.OCH₂C₆H₄-4-CO₂H OH H CO 110. OCH₂C₆H₄-2-tetrazole OH H CO 111.OCH₂C₆H₄-3-tetrazole OH H CO 112. OCH₂C₆H₄-4-tetrazole OH H CO 113.OCH₂-tetrazole H CH₃ CO 114. tetrazole H CH₃ CO 115. NHSO₂CH₃ H CH₃ CO116. OCH₂CO₂Et H CH₃ CO 117. OCH₂CO₂H H CH₃ CO 118. OCH₂CH═CHCO₂Et H CH₃CO 119. OCH₂CH═CHCO₂H H CH₃ CO 120. NHCOCH₂CO₂Et H CH₃ CO 121.NHCOCH₂CO₂H H CH₃ CO 122. OCH₂C₆H₄-2-CO₂Et H CH₃ CO 123.OCH₂C₆H₄-3-CO₂Et H CH₃ CO 124. OCH₂C₆H₄-4-CO₂Et H CH₃ CO 125.OCH₂C₆H₄-2-CO₂H H CH₃ CO 126. OCH₂C₆H₄-3-CO₂H H CH₃ CO 127.OCH₂C₆H₄-4-CO₂H H CH₃ CO 128. OCH₂C₆H₄-2-tetrazole H CH₃ CO 129.OCH₂C₆H₄-3-tetrazole H CH₃ CO 130. OCH₂C₆H₄-4-tetrazole H CH₃ CO 131.OCH₂-tetrazole OH CH₃ CO 132. tetrazole OH CH₃ CO 133. NHSO₂CH₃ OH CH₃CO 134. OCH₂CO₂Et OH CH₃ CO 135. OCH₂CO₂H OH CH₃ CO 136. OCH₂CH═CHCO₂EtOH CH₃ CO 137. OCH₂CH═CHCO₂H OH CH₃ CO 138. NHCOCH₂CO₂Et OH CH₃ CO 139.NHCOCH₂CO₂H OH CH₃ CO 140. OCH₂C₆H₄-2-CO₂Et OH CH₃ CO 141.OCH₂C₆H₄-3-CO₂Et OH CH₃ CO 142. OCH₂C₆H₄-4-CO₂Et OH CH₃ CO 143.OCH₂C₆H₄-2-CO₂H OH CH₃ CO 144. OCH₂C₆H₄-3-CO₂H OH CH₃ CO 145.OCH₂C₆H₄-4-CO₂H OH CH₃ CO 146. OCH₂C₆H₄-2-tetrazole OH CH₃ CO 147.OCH₂C₆H₄-3-tetrazole OH CH₃ CO 148. OCH₂C₆H₄-4-tetrazole OH CH₃ CO

TABLE 2

Ex. # X X″ Y″ Z Q M  1. H Cl H H CH₂CO₂Et SO₂  2. H Cl H H CH₂CO₂H SO₂ 3. Cl Cl H H CH₂CO₂Et SO₂  4. Cl Cl H H CH₂CO₂H SO₂  5. CF₃ Cl H HCH₂CO₂Et SO₂  6. CF₃ Cl H H CH₂CO₂H SO₂  7. OCH₃ Cl H H CH₂CO₂Et SO₂  8.OCH₃ Cl H H CH₂CO₂H SO₂  9. N(CH₃)₂ Cl H H CH₂CO₂Et SO₂  10. N(CH₃)₂ ClH H CH₂CO₂H SO₂  11. CH₃ Cl H H CH₂CO₂Et SO₂  12. CH₃ Cl H H CH₂CO₂H SO₂ 13. H Cl H H CH₂-tetrazole SO₂  14. Cl Cl H H CH₂-tetrazole SO₂  15.CF₃ Cl H H CH₂-tetrazole SO₂  16. OCH₃ Cl H H CH₂-tetrazole SO₂  17.N(CH₃)₂ Cl H H CH₂-tetrazole SO₂  18. CH₃ Cl H H CH₂-tetrazole SO₂  19.H Cl H H CH(CH₃)CO₂Et SO₂  20. H Cl H H CH(CH₃)CO₂H SO₂  21. Cl Cl H HCH(CH₃)CO₂Et SO₂  22. Cl Cl H H CH(CH₃)CO₂H SO₂  23. CF₃ Cl H HCH(CH₃)CO₂Et SO₂  24. CF₃ Cl H H CH(CH₃)CO₂H SO₂  25. OCH₃ Cl H HCH(CH₃)CO₂Et SO₂  26. OCH₃ Cl H H CH(CH₃)CO₂H SO₂  27. N(CH₃)₂ Cl H HCH(CH₃)CO₂Et SO₂  28. N(CH₃)₂ Cl H H CH(CH₃)CO₂H SO₂  29. CH₃ Cl H HCH(CH₃)CO₂Et SO₂  30. CH₃ Cl H H CH(CH₃)CO₂H SO₂  31. H H Cl H CH₂CO₂EtSO₂  32. H H Cl H CH₂CO₂H SO₂  33. Cl H Cl H CH₂CO₂Et SO₂  34. Cl H Cl HCH₂CO₂H SO₂  35. CF₃ H Cl H CH₂CO₂Et SO₂  36. CF₃ H Cl H CH₂CO₂H SO₂ 37. OCH₃ H Cl H CH₂CO₂Et SO₂  38. OCH₃ H Cl H CH₂CO₂H SO₂  39. N(CH₃)₂H Cl H CH₂CO₂Et SO₂  40. N(CH₃)₂ H Cl H CH₂CO₂H SO₂  41. CH₃ H Cl HCH₂CO₂Et SO₂  42. CH₃ H Cl H CH₂CO₂H SO₂  43. H H Cl H CH₂-tetrazole SO₂ 44. Cl H Cl H CH₂-tetrazole SO₂  45. CF₃ H Cl H CH₂-tetrazole SO₂  46.OCH₃ H Cl H CH₂-tetrazole SO₂  47. N(CH₃)₂ H Cl H CH₂-tetrazole SO₂  48.CH₃ H Cl H CH₂-tetrazole SO₂  49. H H Cl H CH(CH₃)CO₂Et SO₂  50. H H ClH CH(CH₃)CO₂H SO₂  51. Cl H Cl H CH(CH₃)CO₂Et SO₂  52. Cl H Cl HCH(CH₃)CO₂H SO₂  53. CF₃ H Cl H CH(CH₃)CO₂Et SO₂  54. CF₃ H Cl HCH(CH₃)CO₂H SO₂  55. OCH₃ H Cl H CH(CH₃)CO₂Et SO₂  56. OCH₃ H Cl HCH(CH₃)CO₂H SO₂  57. N(CH₃)₂ H Cl H CH(CH₃)CO₂Et SO₂  58. N(CH₃)₂ H Cl HCH(CH₃)CO₂H SO₂  59. CH₃ H Cl H CH(CH₃)CO₂Et SO₂  60. CH₃ H Cl HCH(CH₃)CO₂H SO₂  61. H H Cl H CH₂CONH₂ SO₂  62. Cl H Cl H CH₂CONH₂ SO₂ 63. CF₃ H Cl H CH₂CONH₂ SO₂  64. OCH₃ H Cl H CH₂CONH₂ SO₂  65. N(CH₃)₂H Cl H CH₂CONH₂ SO₂  66. CH₃ H Cl H CH₂CONH₂ SO₂  67. H Cl H OH CH₂CO₂EtSO₂  68. H Cl H OH CH₂CO₂H SO₂  69. Cl Cl H OH CH₂CO₂Et SO₂  70. Cl Cl HOH CH₂CO₂H SO₂  71. CF₃ Cl H OH CH₂CO₂Et SO₂  72. CF₃ Cl H OH CH₂CO₂HSO₂  73. OCH₃ Cl H OH CH₂CO₂Et SO₂  74. OCH₃ Cl H OH CH₂CO₂H SO₂  75.N(CH₃)₂ Cl H OH CH₂CO₂Et SO₂  76. N(CH₃)₂ Cl H OH CH₂CO₂H SO₂  77. CH₃Cl H OH CH₂CO₂Et SO₂  78. CH₃ Cl H OH CH₂CO₂H SO₂  79. H Cl H OHCH₂-tetrazole SO₂  80. Cl Cl H OH CH₂-tetrazole SO₂  81. CF₃ Cl H OHCH₂-tetrazole SO₂  82. OCH₃ Cl H OH CH₂-tetrazole SO₂  83. N(CH₃)₂ Cl HOH CH₂-tetrazole SO₂  84. CH₃ Cl H OH CH₂-tetrazole SO₂  85. H Cl H OHCH(CH₃)CO₂Et SO₂  86. H Cl H OH CH(CH₃)CO₂H SO₂  87. Cl Cl H OHCH(CH₃)CO₂Et SO₂  88. Cl Cl H OH CH(CH₃)CO₂H SO₂  89. CF₃ Cl H OHCH(CH₃)CO₂Et SO₂  90. CF₃ Cl H OH CH(CH₃)CO₂H SO₂  91. OCH₃ Cl H OHCH(CH₃)CO₂Et SO₂  92. OCH₃ Cl H OH CH(CH₃)CO₂H SO₂  93. N(CH₃)₂ Cl H OHCH(CH₃)CO₂Et SO₂  94. N(CH₃)₂ Cl H OH CH(CH₃)CO₂H SO₂  95. CH₃ Cl H OHCH(CH₃)CO₂Et SO₂  96. CH₃ Cl H OH CH(CH₃)CO₂H SO₂  97. H Cl H OHCH(CH₂OH)CO₂Et SO₂  98. H Cl H OH CH(CH₂OH)CO₂H SO₂  99. Cl Cl H OHCH(CH₂OH)CO₂Et SO₂ 100. Cl Cl H OH CH(CH₂OH)CO₂H SO₂ 101. CF₃ Cl H OHCH(CH₂OH)CO₂Et SO₂ 102. CF₃ Cl H OH CH(CH₂OH)CO₂H SO₂ 103. OCH₃ Cl H OHCH(CH₂OH)CO₂Et SO₂ 104. OCH₃ Cl H OH CH(CH₂OH)CO₂H SO₂ 105. N(CH₃)₂ Cl HOH CH(CH₂OH)CO₂Et SO₂ 106. N(CH₃)₂ Cl H OH CH(CH₂OH)CO₂H SO₂ 107. CH₃ ClH OH CH(CH₂OH)CO₂Et SO₂ 108. CH₃ Cl H OH CH(CH₂OH)CO₂H SO₂ 109. H Cl HOH CH(CH₂OH)CONH₂ SO₂ 110. Cl Cl H OH CH(CH₂OH)CONH₂ SO₂ 111. CF₃ Cl HOH CH(CH₂OH)CONH₂ SO₂ 112. OCH₃ Cl H OH CH(CH₂OH)CONH₂ SO₂ 113. N(CH₃)₂Cl H OH CH(CH₂OH)CONH₂ SO₂ 114. CH₃ Cl H OH CH(CH₂OH)CONH₂ SO₂ 115. H HCl OH CH₂CO₂Et SO₂ 116. H H Cl OH CH₂CO₂H SO₂ 117. Cl H Cl OH CH₂CO₂EtSO₂ 118. Cl H Cl OH CH₂CO₂H SO₂ 119. CF₃ H Cl OH CH₂CO₂Et SO₂ 120. CF₃ HCl OH CH₂CO₂H SO₂ 121. OCH₃ H Cl OH CH₂CO₂Et SO₂ 122. OCH₃ H Cl OHCH₂CO₂H SO₂ 123. N(CH₃)₂ H Cl OH CH₂CO₂Et SO₂ 124. N(CH₃)₂ H Cl OHCH₂CO₂H SO₂ 125. CH₃ H Cl OH CH₂CO₂Et SO₂ 126. CH₃ H Cl OH CH₂CO₂H SO₂127. H H Cl OH CH₂-tetrazole SO₂ 128. Cl H Cl OH CH₂-tetrazole SO₂ 129.CF₃ H Cl OH CH₂-tetrazole SO₂ 130. OCH₃ H Cl OH CH₂-tetrazole SO₂ 131.N(CH₃)₂ H Cl OH CH₂-tetrazole SO₂ 132. CH₃ H Cl OH CH₂-tetrazole SO₂133. H H Cl OH CH(CH₃)CO₂Et SO₂ 134. H H Cl OH CH(CH₃)CO₂H SO₂ 135. Cl HCl OH CH(CH₃)CO₂Et SO₂ 136. Cl H Cl OH CH(CH₃)CO₂H SO₂ 137. CF₃ H Cl OHCH(CH₃)CO₂Et SO₂ 138. CF₃ H Cl OH CH(CH₃)CO₂H SO₂ 139. OCH₃ H Cl OHCH(CH₃)CO₂Et SO₂ 140. OCH₃ H Cl OH CH(CH₃)CO₂H SO₂ 141. N(CH₃)₂ H Cl OHCH(CH₃)CO₂Et SO₂ 142. N(CH₃)₂ H Cl OH CH(CH₃)CO₂H SO₂ 143. CH₃ H Cl OHCH(CH₃)CO₂Et SO₂ 144. CH₃ H Cl OH CH(CH₃)CO₂H SO₂ 145. H H Cl OHCH₂CONH₂ SO₂ 146. Cl H Cl OH CH₂CONH₂ SO₂ 147. CF₃ H Cl OH CH₂CONH₂ SO₂148. OCH₃ H Cl OH CH₂CONH₂ SO₂ 149. N(CH₃)₂ H Cl OH CH₂CONH₂ SO₂ 150.CH₃ H Cl OH CH₂CONH₂ SO₂ 151. H H Cl OH CH(CH₂OH)CO₂Et SO₂ 152. H H ClOH CH(CH₂OH)CO₂H SO₂ 153. Cl H Cl OH CH(CH₂OH)CO₂Et SO₂ 154. Cl H Cl OHCH(CH₂OH)CO₂H SO₂ 155. CF₃ H Cl OH CH(CH₂OH)CO₂Et SO₂ 156. CF₃ H Cl OHCH(CH₂OH)CO₂H SO₂ 157. OCH₃ H Cl OH CH(CH₂OH)CO₂Et SO₂ 158. OCH₃ H Cl OHCH(CH₂OH)CO₂H SO₂ 159. N(CH₃)₂ H Cl OH CH(CH₂OH)CO₂Et SO₂ 160. N(CH₃)₂ HCl OH CH(CH₂OH)CO₂H SO₂ 161. CH₃ H Cl OH CH(CH₂OH)CO₂Et SO₂ 162. CH₃ HCl OH CH(CH₂OH)CO₂H SO₂ 163. H H Cl OH CH(CH₂OH)CONH₂ SO₂ 164. Cl H ClOH CH(CH₂OH)CONH₂ SO₂ 165. CF₃ H Cl OH CH(CH₂OH)CONH₂ SO₂ 166. OCH₃ H ClOH CH(CH₂OH)CONH₂ SO₂ 167. N(CH₃)₂ H Cl OH CH(CH₂OH)CONH₂ SO₂ 168. CH₃ HCl OH CH(CH₂OH)CONH₂ SO₂ 169. H Cl H H CH₂CO₂Et CO 170. H Cl H H CH₂CO₂HCO 171. Cl Cl H H CH₂CO₂Et CO 172. Cl Cl H H CH₂CO₂H CO 173. CF₃ Cl H HCH₂CO₂Et CO 174. CF₃ Cl H H CH₂CO₂H CO 175. OCH₃ Cl H H CH₂CO₂Et CO 176.OCH₃ Cl H H CH₂CO₂H CO 177. N(CH₃)₂ Cl H H CH₂CO₂Et CO 178. N(CH₃)₂ Cl HH CH₂CO₂H CO 179. CH₃ Cl H H CH₂CO₂Et CO 180. CH₃ Cl H H CH₂CO₂H CO 181.H Cl H H CH₂-tetrazole CO 182. Cl Cl H H CH₂-tetrazole CO 183. CF₃ Cl HH CH₂-tetrazole CO 184. OCH₃ Cl H H CH₂-tetrazole CO 185. N(CH₃)₂ Cl H HCH₂-tetrazole CO 186. CH₃ Cl H H CH₂-tetrazole CO 187. H Cl H HCH(CH₃)CO₂Et CO 188. H Cl H H CH(CH₃)CO₂H CO 189. Cl Cl H H CH(CH₃)CO₂EtCO 190. Cl Cl H H CH(CH₃)CO₂H CO 191. CF₃ Cl H H CH(CH₃)CO₂Et CO 192.CF₃ Cl H H CH(CH₃)CO₂H CO 193. OCH₃ Cl H H CH(CH₃)CO₂Et CO 194. OCH₃ ClH H CH(CH₃)CO₂H CO 195. N(CH₃)₂ Cl H H CH(CH₃)CO₂Et CO 196. N(CH₃)₂ Cl HH CH(CH₃)CO₂H CO 197. CH₃ Cl H H CH(CH₃)CO₂Et CO 198. CH₃ Cl H HCH(CH₃)CO₂H CO 199. H H Cl H CH₂CO₂Et CO 200. H H Cl H CH₂CO₂H CO 201.Cl H Cl H CH₂CO₂Et CO 202. Cl H Cl H CH₂CO₂H CO 203. CF₃ H Cl H CH₂CO₂EtCO 204. CF₃ H Cl H CH₂CO₂H CO 205. OCH₃ H Cl H CH₂CO₂Et CO 206. OCH₃ HCl H CH₂CO₂H CO 207. N(CH₃)₂ H Cl H CH₂CO₂Et CO 208. N(CH₃)₂ H Cl HCH₂CO₂H CO 209. CH₃ H Cl H CH₂CO₂Et CO 210. CH₃ H Cl H CH₂CO₂H CO 211. HH Cl H CH₂-tetrazole CO 212. Cl H Cl H CH₂-tetrazole CO 213. CF₃ H Cl HCH₂-tetrazole CO 214. OCH₃ H Cl H CH₂-tetrazole CO 215. N(CH₃)₂ H Cl HCH₂-tetrazole CO 216. CH₃ H Cl H CH₂-tetrazole CO 217. H H Cl HCH(CH₃)CO₂Et CO 218. H H Cl H CH(CH₃)CO₂H CO 219. Cl H Cl H CH(CH₃)CO₂EtCO 220. Cl H Cl H CH(CH₃)CO₂H CO 221. CF₃ H Cl H CH(CH₃)CO₂Et CO 222.CF₃ H Cl H CH(CH₃)CO₂H CO 223. OCH₃ H Cl H CH(CH₃)CO₂Et CO 224. OCH₃ HCl H CH(CH₃)CO₂H CO 225. N(CH₃)₂ H Cl H CH(CH₃)CO₂Et CO 226. N(CH₃)₂ HCl H CH(CH₃)CO₂H CO 227. CH₃ H Cl H CH(CH₃)CO₂Et CO 228. CH₃ H Cl HCH(CH₃)CO₂H CO 229. H H Cl H CH₂CONH₂ CO 230. Cl H Cl H CH₂CONH₂ CO 231.CF₃ H Cl H CH₂CONH₂ CO 232. OCH₃ H Cl H CH₂CONH₂ CO 233. N(CH₃)₂ H Cl HCH₂CONH₂ CO 234. CH₃ H Cl H CH₂CONH₂ CO 235. H Cl H OH CH₂CO₂Et CO 236.H Cl H OH CH₂CO₂H CO 237. Cl Cl H OH CH₂CO₂Et CO 238. Cl Cl H OH CH₂CO₂HCO 239. CF₃ Cl H OH CH₂CO₂Et CO 240. CF₃ Cl H OH CH₂CO₂H CO 241. OCH₃ ClH OH CH₂CO₂Et CO 242. OCH₃ Cl H OH CH₂CO₂H CO 243. N(CH₃)₂ Cl H OHCH₂CO₂Et CO 244. N(CH₃)₂ Cl H OH CH₂CO₂H CO 245. CH₃ Cl H OH CH₂CO₂Et CO246. CH₃ Cl H OH CH₂CO₂H CO 247. H Cl H OH CH₂-tetrazole CO 248. Cl Cl HOH CH₂-tetrazole CO 249. CF₃ Cl H OH CH₂-tetrazole CO 250. OCH₃ Cl H OHCH₂-tetrazole CO 251. N(CH₃)₂ Cl H OH CH₂-tetrazole CO 252. CH₃ Cl H OHCH₂-tetrazole CO 253. H Cl H OH CH(CH₃)CO₂Et CO 254. H Cl H OHCH(CH₃)CO₂H CO 255. Cl Cl H OH CH(CH₃)CO₂Et CO 256. Cl Cl H OHCH(CH₃)CO₂H CO 257. CF₃ Cl H OH CH(CH₃)CO₂Et CO 258. CF₃ Cl H OHCH(CH₃)CO₂H CO 259. OCH₃ Cl H OH CH(CH₃)CO₂Et CO 260. OCH₃ Cl H OHCH(CH₃)CO₂H CO 261. N(CH₃)₂ Cl H OH CH(CH₃)CO₂Et CO 262. N(CH₃)₂ Cl H OHCH(CH₃)CO₂H CO 263. CH₃ Cl H OH CH(CH₃)CO₂Et CO 264. CH₃ Cl H OHCH(CH₃)CO₂H CO 265. H Cl H OH CH(CH₂OH)CO₂Et CO 266. H Cl H OHCH(CH₂OH)CO₂H CO 267. Cl Cl H OH CH(CH₂OH)CO₂Et CO 268. Cl Cl H OHCH(CH₂OH)CO₂H CO 269. CF₃ Cl H OH CH(CH₂OH)CO₂Et CO 270. CF₃ Cl H OHCH(CH₂OH)CO₂H CO 271. OCH₃ Cl H OH CH(CH₂OH)CO₂Et CO 272. OCH₃ Cl H OHCH(CH₂OH)CO₂H CO 273. N(CH₃)₂ Cl H OH CH(CH₂OH)CO₂Et CO 274. N(CH₃)₂ ClH OH CH(CH₂OH)CO₂H CO 275. CH₃ Cl H OH CH(CH₂OH)CO₂Et CO 276. CH₃ Cl HOH CH(CH₂OH)CO₂H CO 277. H Cl H OH CH(CH₂OH)CONH₂ CO 278. Cl Cl H OHCH(CH₂OH)CONH₂ CO 279. CF₃ Cl H OH CH(CH₂OH)CONH₂ CO 280. OCH₃ Cl H OHCH(CH₂OH)CONH₂ CO 281. N(CH₃)₂ Cl H OH CH(CH₂OH)CONH₂ CO 282. CH₃ Cl HOH CH(CH₂OH)CONH₂ CO 283. H H Cl OH CH₂CO₂Et CO 284. H H Cl OH CH₂CO₂HCO 285. Cl H Cl OH CH₂CO₂Et CO 286. Cl H Cl OH CH₂CO₂H CO 287. CF₃ H ClOH CH₂CO₂Et CO 288. CF₃ H Cl OH CH₂CO₂H CO 289. OCH₃ H Cl OH CH₂CO₂Et CO290. OCH₃ H Cl OH CH₂CO₂H CO 291. N(CH₃)₂ H Cl OH CH₂CO₂Et CO 292.N(CH₃)₂ H Cl OH CH₂CO₂H CO 293. CH₃ H Cl OH CH₂CO₂Et CO 294. CH₃ H Cl OHCH₂CO₂H CO 295. H H Cl OH CH₂-tetrazole CO 296. Cl H Cl OH CH₂-tetrazoleCO 297. CF₃ H Cl OH CH₂-tetrazole CO 298. OCH₃ H Cl OH CH₂-tetrazole CO299. N(CH₃)₂ H Cl OH CH₂-tetrazole CO 300. CH₃ H Cl OH CH₂-tetrazole CO301. H H Cl OH CH(CH₃)CO₂Et CO 302. H H Cl OH CH(CH₃)CO₂H CO 303. Cl HCl OH CH(CH₃)CO₂Et CO 304. Cl H Cl OH CH(CH₃)CO₂H CO 305. CF₃ H Cl OHCH(CH₃)CO₂Et CO 306. CF₃ H Cl OH CH(CH₃)CO₂H CO 307. OCH₃ H Cl OHCH(CH₃)CO₂Et CO 308. OCH₃ H Cl OH CH(CH₃)CO₂H CO 309. N(CH₃)₂ H Cl OHCH(CH₃)CO₂Et CO 310. N(CH₃)₂ H Cl OH CH(CH₃)CO₂H CO 311. CH₃ H Cl OHCH(CH₃)CO₂Et CO 312. CH₃ H Cl OH CH(CH₃)CO₂H CO 313. H H Cl OH CH₂CONH₂CO 314. Cl H Cl OH CH₂CONH₂ CO 315. CF₃ H Cl OH CH₂CONH₂ CO 316. OCH₃ HCl OH CH₂CONH₂ CO 317. N(CH₃)₂ H Cl OH CH₂CONH₂ CO 318. CH₃ H Cl OHCH₂CONH₂ CO 319. H H Cl OH CH(CH₂OH)CO₂Et CO 320. H H Cl OHCH(CH₂OH)CO₂H CO 321. Cl H Cl OH CH(CH₂OH)CO₂Et CO 322. Cl H Cl OHCH(CH₂OH)CO₂H CO 323. CF₃ H Cl OH CH(CH₂OH)CO₂Et CO 324. CF₃ H Cl OHCH(CH₂OH)CO₂H CO 325. OCH₃ H Cl OH CH(CH₂OH)CO₂Et CO 326. OCH₃ H Cl OHCH(CH₂OH)CO₂H CO 327. N(CH₃)₂ H Cl OH CH(CH₂OH)CO₂Et CO 328. N(CH₃)₂ HCl OH CH(CH₂OH)CO₂H CO 329. CH₃ H Cl OH CH(CH₂OH)CO₂Et CO 330. CH₃ H ClOH CH(CH₂OH)CO₂H CO 331. H H Cl OH CH(CH₂OH)CONH₂ CO 332. Cl H Cl OHCH(CH₂OH)CONH₂ CO 333. CF₃ H Cl OH CH(CH₂OH)CONH₂ CO 334. OCH₃ H Cl OHCH(CH₂OH)CONH₂ CO 335. N(CH₃)₂ H Cl OH CH(CH₂OH)CONH₂ CO 336 CH₃ H Cl OHCH(CH₂OH)CONH₂ CO

TABLE 3

Ex. # X″ Z Q n M  1. Et(OCH₂CH₂)_(n)O H H 2 SO₂  2. Et(OCH₂CH₂)_(n)O H H3 SO₂  3. Et(OCH₂CH₂)_(n)O H H 4 SO₂  4. Et(OCH₂CH₂)_(n)O H H 5 SO₂  5.Et(OCH₂CH₂)_(n)O H H 6 SO₂  6. H(OCH₂CH₂)_(n)O H H 2 SO₂  7.H(OCH₂CH₂)_(n)O H H 3 SO₂  8. H(OCH₂CH₂)_(n)O H H 4 SO₂  9.H(OCH₂CH₂)_(n)O H H 5 SO₂  10. H(OCH₂CH₂)_(n)O H H 6 SO₂  11.Et(OCH₂CH₂)_(n)O H H 2 CO  12. Et(OCH₂CH₂)_(n)O H H 3 CO  13.Et(OCH₂CH₂)_(n)O H H 4 CO  14. Et(OCH₂CH₂)_(n)O H H 5 CO  15.Et(OCH₂CH₂)_(n)O H H 6 CO  16. H(OCH₂CH₂)_(n)O H H 2 CO  17.H(OCH₂CH₂)_(n)O H H 3 CO  18. H(OCH₂CH₂)_(n)O H H 4 CO  19.H(OCH₂CH₂)_(n)O H H 5 CO  20. H(OCH₂CH₂)_(n)O H H 6 CO  21.Et(OCH₂CH₂)_(n)O H H 2 SO₂  22. Et(OCH₂CH₂)_(n)O H H 3 SO₂  23.Et(OCH₂CH₂)_(n)O H H 4 SO₂  24. Et(OCH₂CH₂)_(n)O H H 5 SO₂  25.Et(OCH₂CH₂)_(n)O H H 6 SO₂  26. H(OCH₂CH₂)_(n)O H H 2 SO₂  27.H(OCH₂CH₂)_(n)O H H 3 SO₂  28. H(OCH₂CH₂)_(n)O H H 4 SO₂  29.H(OCH₂CH₂)_(n)O H H 5 SO₂  30. H(OCH₂CH₂)_(n)O H H 6 SO₂  31.Et(OCH₂CH₂)_(n)O H H 2 CO  32. Et(OCH₂CH₂)_(n)O H H 3 CO  33.Et(OCH₂CH₂)_(n)O H H 4 CO  34. Et(OCH₂CH₂)_(n)O H H 5 CO  35.Et(OCH₂CH₂)_(n)O H H 6 CO  36. H(OCH₂CH₂)_(n)O H H 2 CO  37.H(OCH₂CH₂)_(n)O H H 3 CO  38. H(OCH₂CH₂)_(n)O H H 4 CO  39.H(OCH₂CH₂)_(n)O H H 5 CO  40. H(OCH₂CH₂)_(n)O H CH₃ 6 CO  41.Et(OCH₂CH₂)_(n)O H CH₃ 2 SO₂  42. Et(OCH₂CH₂)_(n)O H CH₃ 3 SO₂  43.Et(OCH₂CH₂)_(n)O H CH₃ 4 SO₂  44. Et(OCH₂CH₂)_(n)O H CH₃ 5 SO₂  45.Et(OCH₂CH₂)_(n)O H CH₃ 6 SO₂  46. H(OCH₂CH₂)_(n)O H CH₃ 2 SO₂  47.H(OCH₂CH₂)_(n)O H CH₃ 3 SO₂  48. H(OCH₂CH₂)_(n)O H CH₃ 4 SO₂  49.H(OCH₂CH₂)_(n)O H CH₃ 5 SO₂  50. H(OCH₂CH₂)_(n)O H CH₃ 6 SO₂  51.Et(OCH₂CH₂)_(n)O H CH₃ 2 CO  52. Et(OCH₂CH₂)_(n)O H CH₃ 3 CO  53.Et(OCH₂CH₂)_(n)O H CH₃ 4 CO  54. Et(OCH₂CH₂)_(n)O H CH₃ 5 CO  55.Et(OCH₂CH₂)_(n)O H CH₃ 6 CO  56. H(OCH₂CH₂)_(n)O H CH₃ 2 CO  57.H(OCH₂CH₂)_(n)O H CH₃ 3 CO  58. H(OCH₂CH₂)_(n)O H CH₃ 4 CO  59.H(OCH₂CH₂)_(n)O H CH₃ 5 CO  60. H(OCH₂CH₂)_(n)O H CH₃ 6 CO  61.Et(OCH₂CH₂)_(n)O H CH₃ 2 SO₂  62. Et(OCH₂CH₂)_(n)O H CH₃ 3 SO₂  63.Et(OCH₂CH₂)_(n)O H CH₃ 4 SO₂  64. Et(OCH₂CH₂)_(n)O H CH₃ 5 SO₂  65.Et(OCH₂CH₂)_(n)O H CH₃ 6 SO₂  66. H(OCH₂CH₂)_(n)O H CH₃ 2 SO₂  67.H(OCH₂CH₂)_(n)O H CH₃ 3 SO₂  68. H(OCH₂CH₂)_(n)O H CH₃ 4 SO₂  69.H(OCH₂CH₂)_(n)O H CH₃ 5 SO₂  70. H(OCH₂CH₂)_(n)O H CH₃ 6 SO₂  71.Et(OCH₂CH₂)_(n)O H CH₃ 2 CO  72. Et(OCH₂CH₂)_(n)O H CH₃ 3 CO  73.Et(OCH₂CH₂)_(n)O H CH₃ 4 CO  74. Et(OCH₂CH₂)_(n)O H CH₃ 5 CO  75.Et(OCH₂CH₂)_(n)O H CH₃ 6 CO  76. H(OCH₂CH₂)_(n)O H CH₃ 2 CO  77.H(OCH₂CH₂)_(n)O H CH₃ 3 CO  78. H(OCH₂CH₂)_(n)O H CH₃ 4 CO  79.H(OCH₂CH₂)_(n)O H CH₃ 5 CO  80. H(OCH₂CH₂)_(n)O H CH₃ 6 CO  81.Et(OCH₂CH₂)_(n)O OH H 2 SO₂  82. Et(OCH₂CH₂)_(n)O OH H 3 SO₂  83.Et(OCH₂CH₂)_(n)O OH H 4 SO₂  84. Et(OCH₂CH₂)_(n)O OH H 5 SO₂  85.Et(OCH₂CH₂)_(n)O OH H 6 SO₂  86. H(OCH₂CH₂)_(n)O OH H 2 SO₂  87.H(OCH₂CH₂)_(n)O OH H 3 SO₂  88. H(OCH₂CH₂)_(n)O OH H 4 SO₂  89.H(OCH₂CH₂)_(n)O OH H 5 SO₂  90. H(OCH₂CH₂)_(n)O OH H 6 SO₂  91.Et(OCH₂CH₂)_(n)O OH H 2 CO  92. Et(OCH₂CH₂)_(n)O OH H 3 CO  93.Et(OCH₂CH₂)_(n)O OH H 4 CO  94. Et(OCH₂CH₂)_(n)O OH H 5 CO  95.Et(OCH₂CH₂)_(n)O OH H 6 CO  96. H(OCH₂CH₂)_(n)O OH H 2 CO  97.H(OCH₂CH₂)_(n)O OH H 3 CO  98. H(OCH₂CH₂)_(n)O OH H 4 CO  99.H(OCH₂CH₂)_(n)O OH H 5 CO 100. H(OCH₂CH₂)_(n)O OH H 6 CO 101.Et(OCH₂CH₂)_(n)O OH H 2 SO₂ 102. Et(OCH₂CH₂)_(n)O OH H 3 SO₂ 103.Et(OCH₂CH₂)_(n)O OH H 4 SO₂ 104. Et(OCH₂CH₂)_(n)O OH H 5 SO₂ 105.Et(OCH₂CH₂)_(n)O OH H 6 SO₂ 106. H(OCH₂CH₂)_(n)O OH H 2 SO₂ 107.H(OCH₂CH₂)_(n)O OH H 3 SO₂ 108. H(OCH₂CH₂)_(n)O OH H 4 SO₂ 109.H(OCH₂CH₂)_(n)O OH H 5 SO₂ 110. H(OCH₂CH₂)_(n)O OH H 6 SO₂ 111.Et(OCH₂CH₂)_(n)O OH H 2 CO 112. Et(OCH₂CH₂)_(n)O OH H 3 CO 113.Et(OCH₂CH₂)_(n)O OH H 4 CO 114. Et(OCH₂CH₂)_(n)O OH H 5 CO 115.Et(OCH₂CH₂)_(n)O OH H 6 CO 116. H(OCH₂CH₂)_(n)O OH H 2 CO 117.H(OCH₂CH₂)_(n)O OH H 3 CO 118. H(OCH₂CH₂)_(n)O OH H 4 CO 119.H(OCH₂CH₂)_(n)O OH H 5 CO 120. H(OCH₂CH₂)_(n)O OH CH₃ 6 CO 121.Et(OCH₂CH₂)_(n)O OH CH₃ 2 SO₂ 122. Et(OCH₂CH₂)_(n)O OH CH₃ 3 SO₂ 123.Et(OCH₂CH₂)_(n)O OH CH₃ 4 SO₂ 124. Et(OCH₂CH₂)_(n)O OH CH₃ 5 SO₂ 125.Et(OCH₂CH₂)_(n)O OH CH₃ 6 SO₂ 126. H(OCH₂CH₂)_(n)O OH CH₃ 2 SO₂ 127.H(OCH₂CH₂)_(n)O OH CH₃ 3 SO₂ 128. H(OCH₂CH₂)_(n)O OH CH₃ 4 SO₂ 129.H(OCH₂CH₂)_(n)O OH CH₃ 5 SO₂ 130. H(OCH₂CH₂)_(n)O OH CH₃ 6 SO₂ 131.Et(OCH₂CH₂)_(n)O OH CH₃ 2 CO 132. Et(OCH₂CH₂)_(n)O OH CH₃ 3 CO 133.Et(OCH₂CH₂)_(n)O OH CH₃ 4 CO 134. Et(OCH₂CH₂)_(n)O OH CH₃ 5 CO 135.Et(OCH₂CH₂)_(n)O OH CH₃ 6 CO 136. H(OCH₂CH₂)_(n)O OH CH₃ 2 CO 137.H(OCH₂CH₂)_(n)O OH CH₃ 3 CO 138. H(OCH₂CH₂)_(n)O OH CH₃ 4 CO 139.H(OCH₂CH₂)_(n)O OH CH₃ 5 CO 140. H(OCH₂CH₂)_(n)O OH CH₃ 6 CO 141.Et(OCH₂CH₂)_(n)O OH CH₃ 2 SO₂ 142. Et(OCH₂CH₂)_(n)O OH CH₃ 3 SO₂ 143.Et(OCH₂CH₂)_(n)O OH CH₃ 4 SO₂ 144. Et(OCH₂CH₂)_(n)O OH CH₃ 5 SO₂ 145.Et(OCH₂CH₂)_(n)O OH CH₃ 6 SO₂ 146. H(OCH₂CH₂)_(n)O OH CH₃ 2 SO₂ 147.H(OCH₂CH₂)_(n)O OH CH₃ 3 SO₂ 148. H(OCH₂CH₂)_(n)O OH CH₃ 4 SO₂ 149.H(OCH₂CH₂)_(n)O OH CH₃ 5 SO₂ 150. H(OCH₂CH₂)_(n)O OH CH₃ 6 SO₂ 151.Et(OCH₂CH₂)_(n)O OH CH₃ 2 CO 152. Et(OCH₂CH₂)_(n)O OH CH₃ 3 CO 153.Et(OCH₂CH₂)_(n)O OH CH₃ 4 CO 154. Et(OCH₂CH₂)_(n)O OH CH₃ 5 CO 155.Et(OCH₂CH₂)_(n)O OH CH₃ 6 CO 156. H(OCH₂CH₂)_(n)O OH CH₃ 2 CO 157.H(OCH₂CH₂)_(n)O OH CH₃ 3 CO 158. H(OCH₂CH₂)_(n)O OH CH₃ 4 CO 159.H(OCH₂CH₂)_(n)O OH CH₃ 5 CO 160. H(OCH₂CH₂)_(n)O OH CH₃ 6 CO

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise that as specifically described herein.

1. A compound of Formula I or a stereoisomer or pharmaceuticallyacceptable salt thereof:

wherein: X, Y, X′, Y′, X″, and Y″ are independently selected from: H,C₁₋₆ alkyl, halogen, CF₃, O—C₁₋₆ alkyl, NO₂, NR₂, O(CH₂)_(n)CO₂R,OCH₂CH═CHCO₂R, CH₂O(CH₂)_(n)CO₂R, CH₂OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂,CH₂O(CH₂)_(n)PO(OR)₂, NR^(a)(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)PO(OR)₂,NR^(a)CH₂CH═CHCO₂R, NR^(a)SO₂R, NR^(a)CO(CH₂)_(n)CO₂R,NR^(a)CO(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C₆H₄CO₂R,O(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, CH₂O(CH₂)_(n)C₆H₄CO₂R,O(CH₂)_(n)C₆H₄CONR^(a) ₂, O(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a) ₂,O(CH₂)_(n)C₆H₄-tetrazole, CH₂O(CH₂)_(n)C₆H₄CONR^(a) ₂,CH₂O(CH₂)_(n)C₆H₄-tetrazole, O(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole,NR^(a)(CH₂)_(n)C₆H₄CO₂R, CH₂NR^(a)(CH₂)_(n)C₆H₄CO₂R,NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂,CH₂NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂, NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a)₂, NR^(a)(CH₂)_(n)C₆H₄-tetrazole, CH₂NR^(a)(CH₂)_(n)C₆H₄-tetrazole,NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole, C(NH)NR₂, (CH₂)_(n)C(NH)NR₂,O(CH₂)_(n)CONR₂, O(CH₂)_(n)C(NH)NR₂, CH₂O(CH₂)_(n)CONR^(a) ₂,NR^(a)(CH₂)_(n)CONR^(a) ₂, OCH₂CH═CHCONR^(a) ₂, CH₂OCH₂CH═CHCONR^(a) ₂,NR^(a)CH₂CH═CHCONR₂, (CH₂)_(m)-tetrazole, O(CH₂)_(n)-tetrazole,O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, and SO₂NHCH₃; Z is selected from:H, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, O(CH₂CH₂O)_(p)R, OC(O)—C₁₋₆ alkyl,O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)CONH₂,O(CH₂)_(n)C(NH)NH₂, OCH₂CH═CHCONH₂, O(CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, andO(CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole; Q is selected from: H, C₁₋₆alkyl, (CH₂)_(n)-aryl, (CH₂CH₂O)_(p)R, (CH₂)_(n)-heteroaryl,(CH₂)-tetrazole, —CHA(CH₂)_(m)C(O)NR₂, CHA(CH₂)_(m)CO₂R,(CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, (CH₂)_(n)-phenyl-(CH₂)_(m)CONH₂, and(CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole, wherein the heteroaryl, phenyl,and aryl are substituted with 0-3 groups selected from H, C₁₋₄ alkyl,halogen, CF₃, O—C₁₋₄ alkyl, and NO₂; M is C═O or SO₂; R is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; R^(a) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl; A is selected from H, C₁₋₆ alkyl, (CH₂)_(m)C₃₋₆-cycloalkyl,CH₂OH, CH(CH₃)OH, and (CH₂)_(m)-phenyl, wherein the phenyl issubstituted with 0-3 groups selected from H, C₁₋₄ alkyl, halogen, CF₃,O—C₁₋₄ alkyl, and NO₂; p is selected from 2-12; m is selected from 0, 1,2, and 3; and, n is selected from 1, 2, and 3; provided that at leastone of the following is satisfied: (a) at least one of X, Y, X′, Y′, X″,and Y″ is other than H, C₁₋₆ alkyl, halogen, CF₃, O—C₁₋₆ alkyl, NO₂, andNR₂; (b) Z is other than H, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, acetyloxy, andpropionyloxy; or, (c) Q is other than H, C₁₋₆ alkyl,(CH₂)_(n)-heteroaryl, and (CH₂)_(n)-aryl.
 2. A compound of claim 1, or astereoisomer or pharmaceutically acceptable salt thereof, wherein: atleast one of X, Y, X′, Y′, X″, and Y″ is independently selected from:O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, CH₂O(CH₂)_(n)CO₂R, CH₂OCH₂CH═CHCO₂R,O(CH₂)_(n)PO(OR)₂, CH₂O(CH₂)_(n)PO(OR)₂, NR^(a)(CH₂)_(n)CO₂R,NR^(a)(CH₂)_(n)PO(OR)₂, NR^(a)CH₂CH═CHCO₂R, NR^(a)CO(CH₂)_(n)CONR^(a) ₂,NR^(a)SO₂CH₃, NR^(a)CO(CH₂)_(n)CO₂R, O(CH₂)_(n)C₆H₄CO₂R,O(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R, CH₂O(CH₂)_(n)C₆H₄CO₂R, O(CH₂)_(n)C₆H₄CONH₂,O(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C₆H₄-tetrazole,CH₂O(CH₂)_(n)C₆H₄CONH₂, CH₂O(CH₂)_(n)C₆H₄-tetrazole,O(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole, NR^(a)(CH₂)_(n)C₆H₄CO₂R,CH₂NR^(a)(CH₂)_(n)C₆H₄CO₂R, NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CO₂R,NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂, CH₂NR^(a)(CH₂)_(n)C₆H₄CONR^(a) ₂,NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)CONR^(a) ₂, NR^(a)(CH₂)_(n)C₆H₄-tetrazole,CH₂NR^(a)(CH₂)_(n)C₆H₄-tetrazole,NR^(a)(CH₂)_(n)C₆H₄(CH₂)_(n)-tetrazole, C(NH)NR₂, (CH₂)_(n)C(NH)NR₂,O(CH₂)_(n)CONR^(a) ₂, O(CH₂)_(n)C(NH)NH₂, CH₂O(CH₂)_(n)CONR^(a) ₂,NR^(a)(CH₂)_(n)CONH₂, OCH₂CH═CHCONR^(a) ₂, CH₂OCH₂CH═CHCONR^(a) ₂,NR^(a)CH₂CH═CHCONR^(a) ₂, (CH₂)_(m)-tetrazole, O(CH₂)_(n)-tetrazole,O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, and SO₂NHCH₃; the other of X, Y,X′, Y′, X″, and Y″ are independently selected from: H, C₁₋₄ alkyl,halogen, CF₃, O—C₁₋₄ alkyl, NO₂, and NR₂; R is independently selectedfrom H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R^(a) isindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl; Z is selected from: H, C₁₋₄ alkyl, OH, O—C₁₋₄ alkyl, acetyloxy,and propionyloxy; Q is selected from: is selected from H, C₁₋₄ alkyl,(CH₂CH₂O)_(p)R, (CH₂)_(n)-heteroaryl, and (CH₂)_(m)-aryl, wherein theheteroaryl and aryl are substituted with 0-3 groups selected from H,C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, and NO₂; M is C═O or SO₂; p isselected from 2-12; m is independently selected from 0, 1, 2, and 3;and, n is independently selected from 1, 2, and
 3. 3. A compound ofclaim 2, or a stereoisomer or pharmaceutically acceptable salt thereof,wherein: X, Y, X′, Y′, X″, and Y″ are independently selected from: H,C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, NO₂, O(CH₂CH₂O)_(p)R,NR^(a)(CH₂CH₂O)_(p)R, and NR₂; Z is selected from: O(CH₂CH₂O)_(p)R,O(CH₂)_(n)CO₂R, OCH₂CH═CHCO₂R, O(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)CONH₂,O(CH₂)_(n)C(NH)NH₂, OCH₂CH═CHCONH₂, O(CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R, andO(CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole; Q is selected from: H, C₁₋₄alkyl, (CH₂CH₂O)_(p)R, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)-aryl, whereinthe heteroaryl and aryl are substituted with 0-3 groups selected from H,C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl, and NO₂; M is C═O or SO₂; R isindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl; p is selected from 2-12; m is independently selected from 0, 1,2, and 3; and, n is independently selected from 1, 2, and
 3. 4. Acompound of claim 3, or a stereoisomer or pharmaceutically acceptablesalt thereof, wherein: X, Y, X′, Y′, X″, and Y″ are individuallyselected from the following: H, C₁₋₄ alkyl, halogen, CF₃, O—C₁₋₄ alkyl,NO₂, O(CH₂CH₂O)_(p)R, NR^(a)(CH₂CH₂O)_(p)R, and NR₂; Z is selected from:H, C₁₋₄ alkyl, OH, O—C₁₋₄ alkyl, acetyloxy, and propionyloxy; Q isselected from: —(CH₂)_(n)-tetrazole, —CHA(CH₂)_(m)C(O)NHR,CHA(CH₂)_(m)CO₂R, (CH₂)_(n)-phenyl-(CH₂)_(m)CO₂R,(CH₂)_(n)-phenyl-(CH₂)_(m)CONH₂, (CH₂)_(n)-phenyl-(CH₂)_(m)-tetrazole,and (CH₂CH₂O)_(p)R; M is C═O or SO₂; A is selected from H, C₁₋₄ alkyl,(CH₂)_(m)-C₃₋₆-cycloalkyl, CH₂OH, CH(CH₃)OH, (CH₂)_(m)-phenyl, whereinthe phenyl is substituted with 0-3 groups selected from H, C₁₋₄ alkyl,halogen, CF₃, O—C₁₋₄ alkyl, and NO₂; R is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; p is selected from 2-12; mis independently selected from 0, 1, 2, and 3; and, n is independentlyselected from 1, 2, and
 3. 5. A compound of claim 1, wherein thecompound is selected from the compounds of Table 1a, 1b, 1c, 1d, 2, and3 or a stereoisomer or a pharmaceutically acceptable salt thereof.
 6. Apharmaceutical composition, comprising: a compound according to claim 1and a pharmaceutically acceptable carrier.
 7. A method of treating adisease, comprising: administering to a mammal in need thereof atherapeutically effective amount of a compound of according to claim 1,wherein the disease is selected from obesity, diabetes, cardiometabolicdisorders, and a combination thereof.
 8. The method of claim 7, whereinthe cardiometabolic disorder is selected from hypertension anddyslipidemia.
 9. The method of claim 8, wherein the dyslipidemia isselected from low levels of high-density lipoprotein, high levels oflow-density lipoprotein, and high levels of triglycerides.
 10. A methodof treating a co-morbidity of obesity, comprising: administering to amammal in need thereof a therapeutically effective amount of a compoundof claim
 1. 11. The method of claim 10, wherein the co-morbidity isselected from diabetes, Metabolic Syndrome, dementia, and heart disease.12. The method of claim 10, wherein the co-morbidity is selected fromhypertension; gallbladder disease; gastrointestinal disorders; menstrualirregularities; degenerative arthritis; venous statis ulcers; pulmonaryhypoventilation syndrome; sleep apnea; snoring; coronary artery disease;arterial sclerotic disease; pseudotumor cerebri; accident proneness;increased risks with surgeries; osteoarthritis; high cholesterol; and,increased incidence of malignancies of the ovaries, cervix, uterus,breasts, prostrate, and gallbladder.
 13. The method of claim 7, whereinthe diabetes disorder is selected from: Type 1 diabetes, Type 2diabetes, inadequate glucose tolerance, and insulin resistance.
 14. Amethod of treating a disease, comprising: administering to a mammal inneed thereof a therapeutically effective amount of a. a compound ofaccording to claim 1, and b. a second therapeutic agent; wherein thedisease is selected from obesity, diabetes, cardiometabolic disorders,and a combination thereof and the second therapeutic agent is useful fortreating the disease.
 15. The method of claim 14, wherein the secondcomponent is selected from the appetite suppressant sibutramine and thegut lipase inhibitor orlistat.
 16. The method of claim 15, wherein thesecond component is useful for treating diabetes.